Substituted Imidazole 4-Carboxamides as Cholecystokinin-1 Receptor Modulators

ABSTRACT

Certain novel substituted imidazole 4-carboxamides are ligands of the human cholecystokinin receptor and, in particular, are selective ligands of the human cholecystokinin-1 receptor (CCK-1R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the modulation of CCK-1, such as obesity, and diabetes.

BACKGROUND OF THE INVENTION

Obesity is a major health concern in Western societies. It is estimatedthat about 97 million adults in the United States are overweight orobese. Obesity is now recognized as a chronic disease that requirestreatment to reduce its associated health risks. The medical problemsassociated with obesity, which can be serious and life-threatening,include hypertension; type 2 diabetes mellitus; elevated plasma insulinconcentrations; insulin resistance; hyperinsulinemia; glucoseintolerance; dyslipidemias; hyperlipidemia; endometrial, breast,prostate and colon cancer; osteoarthritis; respiratory complications,such as obstructive sleep apnea; cholescystitis; cholelithiasis; gout;gallstones; gall bladder disease; respiratory problems; psychologicaldisorders (such as depression, eating disorders, distorted body imageand low self esteem); arteriosclerosis; heart disease; abnormal heartrhythms; angina pectoris; and heart arrythmias (Kopelman, P. G., Nature404, 635-643 (2000)). Obesity is further associated with premature deathand with a significant increase in mortality and morbidity from stroke,myocardial infarction, congestive heart failure, coronary heart disease,and sudden death. Recent studies have found that obesity and itsassociated health risks also affect children and adolescents. Accordingto the Centers for Disease Control, 15 percent of children andadolescents are defined as overweight and obese, a doubling since theearly 1970s. Important outcomes for the treatment of obesity includeweight loss, and weight management to improve cardiovascular andmetabolic health and to reduce obesity-related morbidity and mortality.It has been shown that 5-10% loss of body weight can substantiallyimprove metabolic values, such as blood glucose, blood pressure, andlipid concentrations, and may reduce morbidity and mortality.

Cholecystokinin (CCK) is a brain-gut peptide that acts as agastrointestinal hormone, neurotransmitter and neuromodulator in thecentral and the peripheral nervous systems. It has been shown that CCKis released from mucosal 1-cells of the duodenum and jejunum in responseto a meal, particularly in response to fat or protein in the meal. Oncereleased, CCK initiates a number of responses coordinated to promotedigestion and regulate food intake, including mediating bile emptyingfrom the gall bladder, regulating the release of digestive enzymes fromthe pancreas, controlling gastric emptying by regulation of the pyloricsphincter, as well as neuronal signaling to the central nervous systemvia vagal afferent neurons. Neuronal CCK is believed to mediate a numberof events within the CNS, including modulating dopaminergicneurotransmission and anxiogenic effects, as well as affecting cognitionand nociception. See, e.g., J. N. Crawley and R. L. Corwin, 1994,Peptides, 15:731-755; N. S. Baber, C. T. Dourish, and D. R. Hill, Pain(1989), 39(3), 307-29; and P. De Tullio, J. Delarge and B. Pirotte,Expert Opinion on Investigational Drugs (2000), 9(1), 129-146.Cholecystokinin has been shown to mediate its diverse hormonal andneuromodulatory functions through two receptor subtypes: the CCK-A(CCK1) and CCK-B (CCK2) subtypes (see, e.g., G. N. Woodruff and J.Hughes, Annu. Rev. Pharmacol. Toxicol. (1991), 31: 469-501). Both CCK-1and CCK-2 receptor subtypes belong to the seven transmembraneG-protein-coupled superfamily of receptors. A number of studies suggestthat CCK mediates its satiety effect through the CCK-1 receptor, whichrelays the postprandial satiety signal via the vagal afferents to theCNS. See, e.g., G. P. Smith et al., Science 213 (1981) pp. 1036-1037;and J. N. Crawley et al., J. Pharmacol. Exp. Ther., 257 (1991) pp.1076-1080. The nucleotide sequences of the peripheral CCK-1 receptor andcentral CCK-1 receptor are identical in humans. See, e.g., S. A. Wank etal., (1994), NY Acad. Sci. 713, pp. 49-66.

It has been reported that cholecystokinin (CCK) inhibits gastricemptying and increases satiety in a variety of species, includinghumans, resulting in a reduction of food intake (Moran, T. H. Physiology& Behavior 2004, 82, 175-180). Selective CCK1R antagonists have beenshown to reverse the anorexigenic effect of CCK thus increasing foodintake and meal size in several species, including humans (Beglinger, C.et. al. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2001, 280,R1149-R1154). Conversely, administration of CCK1R agonists to a varietyof species, including humans, results in a reduction of food intake(Geary, N. Physiology & Behavior 2004, 81, 719-733). Consequently,selective small molecule CCK1R agonists are useful for the treatment orprevention of obesity and related metabolic disorders such as diabetesand dyslipidemia (Woods, S. C. Am. J. Gastrointest. Liver Physiol. 2004,286, G7-13; Moran, T. H., Kinzig, K. P. Am. J. Gastrointest. LiverPhysiol. 2004, 286, G183-G188). In humans, bulimia nervosa has beenlinked with reduced secretion of postprandial CCK (Deylin, M. J. et. al.J. Pharmacol. Exp. Ther. 1987, 241, 100-116), lower CCK concentrationsin cerebrospinal fluid (Lydiard, R. B. et. al. Am. J. Psychiatry 1993,150, 1099-1101), and lower CCK levels in T lymphocytes which couldreflect central CCK secretion levels (Brambilla, F. et. al. PsychiatryResearch 1995, 37, 51-56). Accordingly, CCK1R agonists are also usefulin treating, preventing, or diagnosing bulimia nervosa and relatedeating disorders.

CCK agonists stimulate gallbladder contraction, stimulate pancreaticenzyme secretions, stimulate intestinal blood flow, and affectintestinal motor activity (See Rehfeld, J. F. Best Practice & Res. Clin.Endocrin. & Metab. 2004, 18, 569-586). Consequently, CCK1R agonists areuseful for the treatment, prevention, or diagnosis of disorders relatedto the gall bladder including, but not limited to, cholecystitis(inflammation of the gallbladder) and cholelithiasis (gallstones).Furthermore, CCK agonists are useful for the treatment, prevention, ordiagnosis of disorders related to the pancreas. Finally, CCK1R agonistsare useful for the treatment, prevention, or diagnosis of disordersrelated to the gastrointestinal tract and gastrointestinal motility.

CCK receptors are abundant in the central nervous system, and agonistscan be used for the treatment, prevention, or diagnosis of emotional orsexual behavior disorders and memory disorders (Itoh, S.; et. al. DrugDevelop. Res. 1990, 21, 257-276). Furthermore, CCK agonists can be usedfor the treatment, prevention, or diagnosis of tardive dyskinesia(Nishikawa, T. et. al. Prog. Neuropsycho-pharmnacol. Biol. Psych. 1988,12, 903-812; Bignon, E. et. al. J. Pharm. Exp. Ther. 1999, 289,752-761), Parkinson's disease (Bednar, I. et. al. Biogenic Amine, 1996,12, 275-284), schizophrenia, and psychosis (Crawley, J. N. Trends inPharmacol. Sci., 1991, 12, 232-236).

Imidazole compounds useful for the treatment of obesity and obesityrelated disorders have been disclosed in WO 01/085723, WO 03/040107, WO03/063781, WO 03/007887, WO 2004/094407, WO 2005/009974, WO 2005/040130,WO 2005/063716, WO 2005/095354, US 2005/0054679, US 2005/0124660, US2005/0197377, U.S. Pat. No. 6,960,601, and J. Med. Chem. 2005, 48,1823-1838. Other imidazoles are disclosed in J. Med. Chem. 2005, 48,2638-2645; J. Med. Chem., 2002, 45, 4655-4668; J. Med. Chem. 2000, 43,3168-3185; and J. Med. Chem. 1997, 40, 1634-1647.

Because of the unresolved deficiencies of the various pharmacologicalagents discussed above, there is a continuing need for a weight losstreatment with enhanced efficacy and fewer undesirable side effects. Theinstant invention addresses this problem by providing CCK receptoragonists, and in particular selective agonists of the cholecystokinin-1receptor (CCK-1R), useful in the treatment and prevention of obesity andobesity-related disorders, including diabetes.

It is therefore an object of the present invention to providesubstituted imidazole 4-carboxamides which are selective agonists of thecholecystokinin-1 (CCK-1R) receptor. It is another object of the presentinvention to provide substituted imidazole 4-carboxamides which arecholecystokinin-1 receptor agonists and thereby useful to treat obesity,diabetes, and obesity related disorders. It is another object of thepresent invention to provide pharmaceutical compositions comprising thecholecystokinin-1 receptor agonists of the present invention with apharmaceutically acceptable carrier. It is another object of the presentinvention to provide methods for the treatment or prevention ofdisorders, diseases, or conditions responsive to the activation of thecholecystokinin-1 receptor in a mammal in need thereof by administeringthe compounds and pharmaceutical compositions of the present invention.It is another object of the present invention to provide methods for thetreatment or prevention of obesity, diabetes mellitus, and obesityrelated disorders by administering the compounds and pharmaceuticalcompositions of the present invention to a mammal in need thereof. Theseand other objects will become readily apparent from the detaileddescription that follows.

SUMMARY OF THE INVENTION

The present invention relates to novel substituted imidazole4-carboxamides of formula I:

The compounds of formula I are effective as cholecystokinin receptorligands and are particularly effective as selective ligands of thecholecystokinin-1 receptor. They are therefore useful for the treatmentand/or prevention of disorders responsive to the modulation of thecholecystokinin-1 receptor, such as obesity, diabetes, andobesity-related disorders.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier.

The present invention also relates to methods for the treatment orprevention of disorders, diseases, or conditions responsive to themodulation of the cholecystokinin-1 receptor in a mammal in need thereofby administering the compounds and pharmaceutical compositions of thepresent invention.

The present invention further relates to the use of the compounds of thepresent invention in the preparation of a medicament useful for thetreatment or prevention of disorders, diseases, or conditions responsiveto the modulation of the cholecystokinin-1 receptor in a mammal in needthereof by administering the compounds and pharmaceutical compositionsof the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to substituted imidazole 4-carboxamidesuseful as cholecystokinin receptor modulators, in particular, asselective cholecystokinin-1 receptor agonists. Compounds of the presentinvention are described by formula I:

or a pharmaceutically acceptable salt thereof; wherein

X is N or CR¹⁶;

R¹, R², R³ and R⁴ are each independently selected from the groupconsisting of:

(1) hydrogen,

(2) halogen,

(3) —OH,

(4) —C₁₋₆alkyl,

(5) —C₁₋₆alkoxy,

(6) —SC₁₋₆-alkyl,

(7) —S(O)C₁₋₆-alkyl,

(8) —S(O)₂C₁₋₆-alkyl,

(9) —NHC₁₋₆-alkyl, and

(10) —N(C₁₋₆-alkyl)₂,

wherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents selected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy,or R² and R³ or R³ and R⁴ together with the atoms to which they areattached form a 4-8 membered ring containing 0-2 heteroatomsindependently selected from oxygen, sulfur, and N—R¹⁵, and wherein the4-8 membered ring is unsubstituted or substituted with a substituentselected from OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy;R⁵, R⁶ and R⁷ are each independently selected from the group consistingof:

(1) hydrogen,

(2) halogen,

(3) —OH,

(4) —C₁₋₆alkyl, and

(5) —C₁₋₆alkoxy,

wherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents independently selected from halogen, —OH, C₁₋₆alkyl,and C₁₋₆alkoxy,or R⁵ and R⁶ or R⁶ and R⁷ together with the atoms to which they areattached form a 4-8 membered ring containing 0-2 heteroatomsindependently selected from oxygen, sulfur, and N—R¹⁵, and wherein the4-8 membered ring is unsubstituted or substituted with a substituentselected from OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy;R⁸ is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl,

(4) —C₁₋₆alkoxy, and

(5) —C₃₋₆cycloalkyl;

R⁹ and R¹⁶ are each independently selected from the group consisting of:

(1) hydrogen,

(2) -(CH₂)_(n)CF₃,

(3) -(CH₂)_(n)OH,

(4) -(CH₂)_(n)CN,

(5) -C₁₋₆alkyl,

(6) -C₁₋₆alkoxy,

(7) -(CH₂)_(n)C₃₋₈cycloalkyl,

(8) -(CH₂)_(n)NR¹¹R¹²,

(9) -a 5-10 membered aromatic monocyclic or bicyclic heterocyclic ring,

(10) phenyl,

(11) -C₂₋₆alkene-CO₂R¹²,

(12) -(CH₂)_(n)C(O)R¹²,

(13) -(CH₂)_(n)CO₂R¹²,

(14) -(CH₂)_(n)OC(O)R¹²,

(15) -(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,

(16) -(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹²,

(17) -(CH₂)_(n)C(O)NR¹¹R¹²,

(18) -(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹²,

(19) -(CH₂)_(n)NR¹¹C(O)R¹²,

(20) -(CH₂)_(n)NR¹¹C(O)NR¹¹R¹²,

(21) -(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹²,

(22) -(CH₂)_(n)NR¹¹CO₂R¹², and

(23) -(CH₂)_(n)NR¹¹SO₂R¹²,

wherein alkyl, alkene, alkoxy, cycloalkyl, the heterocyclic ring, phenyland —(CH₂), are unsubstituted or substituted with one to eightsubstituents selected from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy,phenyl, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, provided that at least one of R⁹ and R¹⁶ is selected fromthe group consisting of: —C₂₋₆alkene-CO₂R¹², —(CH₂)_(n)C(O)R¹²,—(CH₂)_(n)CO₂R¹², —(CH₂)_(n)OC(O)R¹², —(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹C(O)R¹²,—(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², —(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)NR¹¹CO₂R¹², and —(CH₂)_(n)NR¹¹SO₂R¹²; each R¹⁰ isindependently selected from the group consisting of:

(1) aryl, and

(2) heteroaryl,

wherein each aryl and heteroaryl ring is unsubstituted or substitutedwith one to four R¹⁴ substituents;each R¹¹, R¹² and R¹³ is independently selected from the groupconsisting of:

(1) hydrogen,

(2) —C₁₋₈alkyl,

(3) —(CH₂)_(n)OH,

(4) —(CH₂)_(n)C₃₋₈cycloalkyl,

(5) —(CH₂)_(n)C₂₋₈heterocycloalkyl,

(6) —(CH₂)_(n)aryl, and

(7) —(CH₂)_(n)heteroaryl,

wherein alkyl, cycloalkyl, heterocycloalkyl, and —(CH₂)_(n) areunsubstituted or substituted with one to eight substituents selectedfrom oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein aryl and heteroaryl areunsubstituted or substituted with one to eight substituentsindependently selected from halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy,—(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, or R¹¹ and R¹² together with the nitrogen to which theyare attached form a 4-8 membered heterocyclic ring containing 0-2additional heteroatoms selected from oxygen, sulfur, and NR¹⁵, andwherein the 4-8 membered heterocyclic ring is unsubstituted orsubstituted with one to five substituents independently selected fromoxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl;each R¹⁴ is independently selected from the group consisting of:

(1) hydrogen,

(2) —(CH₂)_(n)halogen,

(3) —(CH₂)_(n)CN,

(4) —(CH₂)_(n)NO₂,

(5) —(CH₂)_(n)OR¹³,

(6) —C₂₋₆alkene-CO₂R¹²,

(7) —(CH₂)_(n)COR¹³,

(8) —(CH₂)_(n)CO₂R¹³,

(9) —(CH₂)_(n)C(O)NR¹¹R¹²,

(10) —(CH₂)_(n)CONR¹¹COR¹³,

(11) —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹³,

(12) —(CH₂)_(n)C(O)NR¹¹CH(CO₂R¹³)₂,

(13) —(CH₂)_(n)NR¹¹R¹²,

(14) —(CH₂)_(n)NR¹³C(O)NR¹¹R¹²,

(15) —(CH₂)_(n)NR¹³C(O)R¹³,

(16) —(CH₂)_(n)OC(O)NR¹¹R¹²,

(17) —(CH₂)_(n)NR¹³CO₂R¹³,

(18) —(CH₂)_(n)NR¹³SO₂R¹³,

(19) —(CH₂)_(n)SO₂NR¹¹R¹³,

(20) —(CH₂)_(n)SO₂R¹³,

(21) —(CH₂)_(n)SO₃H,

(22) —(CH₂)_(n)PO₂R¹³,

(23) —(CH₂)_(n)PO₃H,

(24) —C₁₋₆alkyl,

(25) —(CH₂)_(n)aryl,

(26) —(CH₂)_(n)heteroaryl,

(27) —(CH₂)_(n)C₂₋₈heterocycloalkyl, and

(28) —(CH₂)_(n)C₃₋₈cycloalkyl,

wherein alkyl, cycloalkyl, heterocycloalkyl, and —(CH₂)_(n) areunsubstituted or substituted with one to five substituents selected fromoxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein alkene, aryland heteroaryl are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl;each R¹⁵ is independently selected from the group consisting of:

(1) hydrogen,

(2) —C₁₋₆alkyl,

(3) —C₃₋₈cycloalkyl,

(4) —SO₂R¹²,

(5) —COR¹³, and

(6) —CO₂R¹²,

wherein alkyl and cycloalkyl are unsubstituted or substituted with oneto six substituents selected from halogen, —OH, and —(CH₂)_(n)CO₂H;each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; andeach q is independently 1, 2, 3 or 4.

In a further embodiment of the compounds of the present invention, thereare provided compounds of formula II:

or a pharmaceutically acceptable salt thereof; wherein

X is N or CR¹⁶; Y is N or CR¹⁴;

R¹, R², R³ and R⁴ are each independently selected from the groupconsisting of:

(1) hydrogen,

(2) halogen,

(3) —OH,

(4) —C₁₋₆alkyl,

(5) —C₁₋₆alkoxy,

(6) —SC₁₋₆-alkyl,

(7) —S(O)C₁₋₆-alkyl,

(8) —S(O)₂C₁₋₆-alkyl,

(9) —NHC₁₋₆-alkyl, and

(10) —N(C₁₋₆-alkyl)₂,

wherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents selected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy,or R² and R³ or R³ and R⁴ together with the atoms to which they areattached form a 4-8 membered ring containing 0-2 heteroatomsindependently selected from oxygen, sulfur, and N—R¹⁵, and wherein the4-8 membered ring is unsubstituted or substituted with a substituentselected from OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy;R⁵, R⁶ and R⁷ are each independently selected from the group consistingof:

(1) hydrogen,

(2) halogen,

(3) —OH,

(4) —C₁₋₆alkyl, and

(5) —C₁₋₆alkoxy,

wherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents independently selected from halogen, —OH, C₁₋₆alkyl,and C₁₋₆alkoxy;R⁸ is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl,

(4) —C₁₋₆alkoxy, and

(5) —C₃₋₆cycloalkyl;

R⁹ and R¹⁶ are each independently selected from the group consisting of:

(1) hydrogen,

(2) -(CH₂)_(n)CF₃,

(3) -(CH₂)_(n)OH,

(4) -(CH₂)_(n)CN,

(5) -C₁₋₆alkyl,

(6) -C₁₋₆alkoxy,

(7) -(CH₂)_(n)C₃₋₈cycloalkyl,

(8) -(CH₂)_(n)NR¹¹R¹²,

(9) -a 5-10 membered aromatic monocyclic or bicyclic heterocyclic ring,

(10) phenyl,

(11) -C₂₋₆alkene-CO₂R¹²,

(12) -(CH₂)_(n)C(O)R¹²,

(13) -(CH₂)_(n)CO₂R¹²,

(14) -(CH₂)_(n)OC(O)R¹²,

(15) -(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,

(16) -(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹²,

(17) -(CH₂)_(n)C(O)NR¹¹R¹²,

(18) -(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹¹,

(19) -(CH₂)_(n)NR¹¹C(O)R¹²,

(20) -(CH₂)_(n)NR¹¹C(O)NR¹¹R¹²,

(21) -(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹²,

(22) -(CH₂)_(n)NR¹¹CO₂R¹², and

(23) -(CH₂)_(n)NR¹¹SO₂R¹²,

wherein alkyl, alkene, alkoxy, cycloalkyl, the heterocyclic ring, phenyland —(CH₂)_(n) are unsubstituted or substituted with one to eightsubstituents selected from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy,phenyl, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, provided that at least one of R⁹ and R¹⁶ is selected fromthe group consisting of: —C₂₋₆alkene-CO₂R¹², —(CH₂)_(n)C(O)R¹²,—(CH₂)_(n)CO₂R¹², —(CH₂)_(n)OC(O)R¹², —(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹C(O)R¹²,—(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², —(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)NR¹¹CO₂R¹², and —(CH₂)_(n)NR¹¹SO₂R¹²;each R¹¹, R¹² and R¹³ is independently selected from the groupconsisting of:

(1) hydrogen,

(2) —C₁₋₈alkyl,

(3) —(CH₂)_(n)OH,

(4) —(CH₂)_(n)C₃₋₈cycloalkyl,

(5) —(CH₂)_(n)C₂₋₈heterocycloalkyl,

(6) —(CH₂)_(n)aryl, and

(7) —(CH₂)_(n)heteroaryl,

wherein alkyl, cycloalkyl, heterocycloalkyl, and —(CH₂)_(n) areunsubstituted or substituted with one to eight substituents selectedfrom oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein aryl and heteroaryl areunsubstituted or substituted with one to eight substituentsindependently selected from halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy,—(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, or R¹¹ and R¹² together with the nitrogen to which theyare attached form a 4-8 membered heterocyclic ring containing 0-2additional heteroatoms selected from oxygen, sulfur, and NR¹⁵, andwherein the 4-8 membered heterocyclic ring is unsubstituted orsubstituted with one to five substituents independently selected fromoxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,7(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl;each R¹⁴ is independently selected from the group consisting of:

(1) hydrogen,

(2) —(CH₂)_(n)halogen,

(3) —(CH₂)_(n)CN,

(4) —(CH₂)_(n)NO₂,

(5) —(CH₂)_(n)OR¹³,

(6) —C₂₋₆alkene-CO₂R¹²,

(7) —(CH₂)_(n)COR¹³,

(8) —(CH₂)_(n)CO₂R¹³,

(9) —(CH₂)_(n)C(O)NR¹¹R¹²,

(10) —(CH₂)_(n)CONR¹¹COR¹³,

(11) —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹³,

(12) —(CH₂)_(n)C(O)NR¹¹CH(CO₂R¹³)₂,

(13) —(CH₂)_(n)NR¹¹R¹²,

(14) —(CH₂)_(n)NR¹³C(O)NR¹¹R¹²,

(15) —(CH₂)_(n)NR¹³C(O)R¹³,

(16) —(CH₂)_(n)OC(O)NR¹¹R¹²,

(17) —(CH₂)_(n)NR¹³CO₂R¹³,

(18) —(CH₂)_(n)NR¹³SO₂R¹³,

(19) —(CH₂)_(n)SO₂NR¹¹R¹²,

(20) —(CH₂)_(n)SO₂R¹³,

(21) —(CH₂)_(n)SO₃H,

(22) —(CH₂)_(n)PO₂R¹³,

(23) —(CH₂)_(n)PO₃H,

(24) —C₁₋₆alkyl,

(25) —(CH₂)_(n)aryl,

(26) —(CH₂)_(n)heteroaryl,

(27) —(CH₂)_(n)C₂₋₈heterocycloalkyl, and

(28) —(CH₂)_(n)C₃₋₈cycloalkyl,

wherein alkyl, cycloalkyl, heterocycloalkyl, and —(CH₂)_(n) areunsubstituted or substituted with one to five substituents selected fromoxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein alkene, aryland heteroaryl are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₇₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl;each R¹⁵ is independently selected from the group consisting of:

(1) hydrogen,

(2) —C₁₋₆alkyl,

(3) —C₃₋₈cycloalkyl,

(4) —SO₂R¹²,

(5) —COR¹³, and

(6) —CO₂R¹²,

wherein alkyl and cycloalkyl are unsubstituted or substituted with oneto six substituents selected from halogen, —OH, and —(CH₂)_(n)CO₂H;each m is independently 0, 1, 2, 3 or 4;each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8;each p is independently 0, 1, 2, or 3; andeach q is independently 1, 2, 3 or 4.

In a further embodiment of the compounds of the present invention, thereare provided compounds of formula III:

or a pharmaceutically acceptable salt thereof; wherein

Y is N or CR¹⁴;

R², R³ and R⁴ are each independently selected from the group consistingof:

(1) hydrogen,

(2) halogen,

(3) —OH,

(4) —C₁₋₆alkyl,

(5) —C₁₋₆alkoxy,

(6) —SC₁₋₆-alkyl,

(7) —S(O)C₁₋₆-alkyl,

(8) —S(O)₂C₁₋₆-alkyl,

(9) —NHC₁₋₆-alkyl, and

(10) —N(C₁₋₆-alkyl)₂,

wherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents selected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy,and wherein R² and R³ or R³ and R⁴ together with the atoms to which theyare attached may form a 4-8 membered ring containing 0-2 heteroatomsindependently selected from oxygen, sulfur, and N—R¹⁵, and wherein the4-8 membered ring is unsubstituted or substituted with a substituentselected from OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy;R⁵, R⁶ and R⁷ are each independently selected from the group consistingof:

(1) hydrogen,

(2) halogen,

(3) —OH,

(4) —C₁₋₆alkyl, and

(5) —C₁₋₆alkoxy,

wherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents independently selected from halogen, —OH, C₁₋₆alkyl,and C₁₋₆alkoxy;R⁸ is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl,

(4) —C₁₋₆alkoxy, and

(5) —C₃₋₆cycloalkyl;

R⁹ is independently selected from the group consisting of:

(1) —C₂₋₆alkene-CO₂R¹²,

(2) —(CH₂)_(n)C(O)R¹²,

(3) —(CH₂)_(n)CO₂R¹²,

(4) —(CH₂)_(n)OC(O)R¹²,

(5) —(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,

(6) —(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹²,

(7) —(CH₂)_(n)C(O)NR¹¹R¹²,

(8) —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹²,

(9) —(CH₂)_(n)NR¹¹C(O)R¹²,

(10) —(CH₂)_(n)NR¹¹C(O)NR¹¹R¹²,

(11) —(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹²,

(12) —(CH₂)_(n)NR¹¹CO₂R¹², and

(13) —(CH₂)_(n)NR¹¹SO₂R¹²,

wherein alkene and —(CH₂)_(n) are unsubstituted or substituted with oneto eight substituents selected from oxo, halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, phenyl, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃,—(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and—(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl;

each R¹¹, R¹² and R¹³ is independently selected from the groupconsisting of:

(1) hydrogen,

(2) —C₁₋₈alkyl,

(3) —(CH₂)_(n)OH,

(4) —(CH₂)_(n)C₃₋₈cycloalkyl,

(5) —(CH₂)_(n)C₂₋₈ heterocycloalkyl,

(6) —(CH₂)_(n)aryl, and

(7) —(CH₂)_(n)heteroaryl,

wherein alkyl, cycloalkyl, heterocycloalkyl, and —(CH₂), areunsubstituted or substituted with one to eight substituents selectedfrom oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein aryl and heteroaryl areunsubstituted or substituted with one to eight substituentsindependently selected from halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy,—(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, or R¹¹ and R¹² together with the nitrogen to which theyare attached form a 4-8 membered heterocyclic ring containing 0-2additional heteroatoms selected from oxygen, sulfur, and NR¹⁵, andwherein the 4-8 membered heterocyclic ring is unsubstituted orsubstituted with one to five substituents independently selected fromoxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl;each R¹⁴ is independently selected from the group consisting of:

(1) hydrogen,

(2) —(CH₂)_(n)halogen,

(3) —(CH₂)_(n)CN,

(4) —(CH₂)_(n)NO₂,

(5) —(CH₂)_(n)OR¹³,

(6) —C₂₋₆alkene-CO₂R¹²,

(7) —(CH₂)_(n)COR¹³,

(8) —(CH₂)_(n)CO₂R¹³,

(9) —(CH₂)_(n)C(O)NR¹¹R¹²,

(10) —(CH₂)_(n)CONR¹¹COR¹³,

(11) —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹³,

(12) —(CH₂)_(n)C(O)NR¹¹CH(CO₂R¹³)₂,

(13) —(CH₂)_(n)NR¹¹R¹²,

(14) —(CH₂)_(n)NR¹³C(O)NR¹¹R¹²,

(15) —(CH₂)_(n)NR¹³C(O)R¹³,

(16) —(CH₂)_(n)OC(O)NR¹¹R¹²,

(17) —(CH₂)_(n)NR¹³CO₂R¹³,

(18) —(CH₂)_(n)NR¹³SO₂R¹³,

(19) —(CH₂)_(n)SO₂NR¹¹R¹²,

(20) —(CH₂)_(n)SO₂R¹³,

(21) —(CH₂)_(n)SO₃H,

(22) —(CH₂)_(n)PO₂R¹³,

(23) —(CH₂)_(n)PO₃H,

(24) —C₁₋₆alkyl,

(25) —(CH₂)_(n)aryl,

(26) —(CH₂)_(n)heteroaryl,

(27) —(CH₂)_(n)C₂₋₈heterocycloalkyl, and

(28) —(CH₂)_(n)C₃₋₈cycloalkyl,

wherein alkyl, cycloalkyl, heterocycloalkyl, and —(CH₂), areunsubstituted or substituted with one to five substituents selected fromoxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein alkene, aryland heteroaryl are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl;each R¹⁵ is independently selected from the group consisting of:

(1) hydrogen,

(2) —C₁₋₆alkyl, unsubstituted or substituted with one to six halogens,

(3) —C₃₋₈cycloalkyl, unsubstituted or substituted with one to sixhalogens,

(4) —SO₂R¹²,

(5) —COR¹², and

(6) —CO₂R¹²;

each m is independently 0, 1, 2, 3 or 4;each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8;each p is independently 0, 1, 2, or 3; andeach q is independently 1, 2, 3 or 4.

In a further embodiment of the compounds of the present invention, thereare provided compounds of formula IV:

or a pharmaceutically acceptable salt thereof; wherein

Y is N or CR¹⁴;

R², R³ and R⁴ are each independently selected from the group consistingof:

(1) hydrogen,

(2) halogen,

(3) —OH,

(4) —C₁₋₆alkyl,

(5) —C₁₋₆alkoxy,

(6) —SC₁₋₆-alkyl,

(7) —S(O)C₁₋₆-alkyl,

(8) —S(O)₂C₁₋₆alkyl,

(9) —NHC₁₋₆-alkyl, and

(10) —N(C₁₋₆-alkyl)₂,

wherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents selected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy,or R² and R³ or R³ and R⁴ together with the atoms to which they areattached may form a 4-8 membered ring containing 0-2 heteroatomsindependently selected from oxygen, sulfur, and N—R¹⁵, and wherein the4-8 membered ring is unsubstituted or substituted with a substituentselected from OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy;R⁵, R⁶ and R⁷ are each independently selected from the group consistingof:

(1) hydrogen,

(2) halogen,

(3) —OH,

(4) —C₁₋₆alkyl, and

(5) —C₁₋₆alkoxy,

wherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents independently selected from halogen, —OH, C₁₋₆alkyl,and C₁₋₆alkoxy;R⁸ is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl,

(4) —C₁₋₆alkoxy, and

(5) —C₃₋₆cycloalkyl;

R⁹ and R¹⁶ are each independently selected from the group consisting of:

(1) hydrogen,

(2) -(CH₂)_(n)CF₃,

(3) -(CH₂)_(n)OH,

(4) -(CH₂)_(n)CN,

(5) -C₁₋₆alkyl,

(6) -C₁₋₆alkoxy,

(7) -(CH₂)_(n)C₃₋₈cycloalkyl,

(8) -(CH₂)_(n)NR¹¹R¹²,

(9) -a 5-10 membered aromatic monocyclic or bicyclic heterocyclic ring,

(10) phenyl,

(11) -C₂₋₆alkene-CO₂R¹²,

(12) -(CH₂)_(n)C(O)R¹²,

(13) -(CH₂)_(n)CO₂R¹²,

(14) -(CH₂)_(n)OC(O)R¹²,

(15) -(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,

(16) -(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹²,

(17) -(CH₂)_(n)C(O)NR¹¹R¹²,

(18) -(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹²,

(19) -(CH₂)_(n)NR¹¹C(O)R¹²,

(20) -(CH₂)_(n)NR¹¹C(O)NR¹¹R¹²,

(21) -(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹²,

(22) -(CH₂)_(n)NR¹¹CO₂R¹², and

(23) -(CH₂)_(n)NR¹¹SO₂R¹²,

wherein alkyl, alkene, alkoxy, cycloalkyl, the heterocyclic ring, phenyland —(CH₂)_(n) are unsubstituted or substituted with one to eightsubstituents selected from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy,phenyl, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, provided that at least one of R⁹ and R¹⁶ is selected fromthe group consisting of: —C₂₋₆alkene-CO₂R¹², —(CH₂)_(n)C(O)R¹²,—(CH₂)_(n)CO₂R¹², —(CH₂)_(n)OC(O)R¹², —(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹C(O)R¹²,—(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², —(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)NR¹¹CO₂R¹², and —(CH₂)_(n)NR¹¹SO₂R¹²;each R¹¹, R¹² and R¹³ is independently selected from the groupconsisting of:

(1) hydrogen,

(2) —C₁₋₈alkyl,

(3) —(CH₂)_(n)OH,

(4) —(CH₂)_(n)C₃₋₈cycloalkyl,

(5) —(CH₂)_(n)C₂₋₈heterocycloalkyl,

(6) —(CH₂)_(n)aryl, and

(7) —(CH₂)_(n)heteroaryl,

wherein alkyl, cycloalkyl, heterocycloalkyl, and —(CH₂), areunsubstituted or substituted with one to eight substituents selectedfrom oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein aryl and heteroaryl areunsubstituted or substituted with one to eight substituentsindependently selected from halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy,—(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, or R¹¹ and R¹² together with the nitrogen to which theyare attached form a 4-8 membered heterocyclic ring containing 0-2additional heteroatoms selected from oxygen, sulfur, and NR¹⁵, andwherein the 4-8 membered heterocyclic ring is unsubstituted orsubstituted with one to five substituents independently selected fromoxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl;each R¹⁴ is independently selected from the group consisting of:

(1) hydrogen,

(2) —(CH₂)_(n)halogen,

(3) —(CH₂)_(n)CN,

(4) —(CH₂)_(n)NO₂,

(5) —(CH₂)_(n)OR¹³,

(6) —C₂₋₆alkene-CO₂R¹²,

(7) —(CH₂)_(n)COR¹³,

(8) —(CH₂)_(n)CO₂R¹³,

(9) —(CH₂)_(n)C(O)NR¹¹R¹²,

(10) —(CH₂)_(n)CONR¹¹R¹³,

(11) —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹³,

(12) —(CH₂)_(n)C(O)NR¹¹CH(CO₂R¹³)₂,

(13) —(CH₂)_(n)NR¹¹R¹²,

(14) —(CH₂)_(n)NR¹³C(O)NR¹¹R¹²,

(15) —(CH₂) NR¹³C(O)R¹³,

(16) —(CH₂)_(n)OC(O)NR¹¹R¹²,

(17) —(CH₂)_(n)NR¹³CO₂R¹³,

(18) —(CH₂)_(n)NR¹³SO₂R¹³,

(19) —(CH₂)_(n)SO₂NR¹¹R¹²,

(20) —(CH₂)_(n)SO₂R¹³,

(21) —(CH₂)_(n)SO₃H,

(22) —(CH₂)_(n)PO₂R¹³,

(23) —(CH₂)_(n)PO₃H,

(24) —C₁₋₆alkyl,

(25) —(CH₂)_(n)aryl,

(26) —(CH₂)_(n)heteroaryl,

(27) —(CH₂)_(n)C₂₋₈heterocycloalkyl, and

(28) —(CH₂)_(n)C₃₋₈cycloalkyl,

wherein alkyl, cycloalkyl, heterocycloalkyl, and —(CH₂)_(n) areunsubstituted or substituted with one to five substituents selected fromoxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein alkene, aryland heteroaryl are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl;each R¹⁵ is independently selected from the group consisting of:

(1) hydrogen,

(2) —C₁₋₆alkyl, unsubstituted or substituted with one to six halogens,

(3) —C₃₋₈cycloalkyl, unsubstituted or substituted with one to sixhalogens,

(4) —SO₂R¹²,

(5) —COR¹², and

(6) —CO₂R¹²;

each m is independently 0, 1, 2, 3 or 4;each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8;each p is independently 0, 1, 2, or 3; andeach q is independently 1, 2, 3 or 4.

In one class of the embodiments, X is N or CR⁶. In a subclass of thisclass, X is N. In another subclass of this class, X is CR¹⁶. In anothersubclass of this class, X is CH, provided that R⁹ is not hydrogen.

In another class of the embodiments, Y is N or CR¹⁴. In a subclass ofthis class, Y is N. In another subclass of this class, Y is CR¹⁴. Inanother subclass of this class, Y is CH.

In another class of the embodiments, R¹, R², R³ and R⁴ are eachindependently selected from the group consisting of: hydrogen, halogen,—OH, —C₁₋₆alkyl, and —C₁₋₆alkoxy, wherein alkyl and alkoxy areunsubstituted or substituted with one to five substituents selected fromhalogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy, or R² and R³ or R³ and R⁴together with the atoms to which they are attached form a 4-8 memberedring containing 0-2 heteroatoms independently selected from oxygen,sulfur, and N—R¹⁵, and wherein the 4-8 membered ring is unsubstituted orsubstituted with a substituent selected from OH, halogen, C₁₋₆alkyl, andC₁₋₆alkoxy.

In another class of the embodiments, R¹, R², R³ and R⁴ are eachindependently selected from the group consisting of: hydrogen, halogen,—OH, —C₁₋₆alkyl, —C₁₋₆alkoxy, and —SC₁₋₆-alkyl, —S(O)C₁₋₆alkyl,—S(O)₂C₁₋₆-alkyl, —NHC₁₋₆-alkyl, and —N(C₁₋₆-alkyl)₂, wherein alkyl andalkoxy are unsubstituted or substituted with one to five substituentsselected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy, and wherein R² andR³ or R³ and R⁴ together with the atoms to which they are attached forma 4-8 membered ring containing 0-2 heteroatoms independently selectedfrom oxygen, sulfur, and N—R¹⁵, and wherein the 4-8 membered ring isunsubstituted or substituted with a substituent selected from OH,halogen, C₁₋₆alkyl, and C₁₋₆alkoxy.

In a subclass of this class, R¹ is selected from the group consistingof: hydrogen, halogen, —OH, —C₁₋₆alkyl, —C₁₋₆alkoxy, —SC₁₋₆alkyl, and—NHC₁₋₆-alkyl, wherein alkyl and alkoxy are unsubstituted or substitutedwith one to five substituents selected from halogen, —OH, C₁₋₆alkyl, andC₁₋₆alkoxy. In another subclass of this class, R¹ is hydrogen. Inanother subclass of this class, R¹ is selected from —OH, —C₁₋₆alkyloptionally substituted with fluoride, —OC₁₋₆alkyl optionally substitutedwith fluoride, hydroxy, and halogen. In another subclass of this class,R¹ is selected from hydrogen, halogen, and —OCH₃. In another subclass ofthis class, R¹ is selected from —OH, —C₁₋₆alkyl, and —C₁₋₆alkoxy,wherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents selected from halogen, —OH, C₁₋₆alkyl, and C₁₋₆alkoxy.In another subclass of this class, R¹ is selected from hydrogen, —OCH₃,and OCH₂CH₃. In another subclass of this class, R¹ is hydrogen.

In a subclass of this class, R² is selected from the group consistingof: hydrogen, —OH, halogen, —C₁₋₆alkyl optionally substituted withfluoride, and —OC₁₋₆alkyl optionally substituted with fluoride. Inanother subclass of this class, R² is selected from hydrogen, —OCH₃,—OCH₂CH₃, —OH, —O(CH)(CH₃)₂, CH₂CH₃, —OCH₂CF₃, and fluoride. In anothersubclass of this subclass, R² is selected from hydrogen, —OCH₃, and—OCH₂CH₃. In another subclass, R² is —OCH₂CH₃. In another subclass, R²is —OCH₃. In another subclass, R² is hydrogen.

In a subclass of this class, R³ is selected from the group consistingof: hydrogen, —OH, halogen, —C₁₋₆alkyl optionally substituted withfluoride, and —OC₁₋₆alkyl optionally substituted with fluoride. Inanother subclass of this class, R³ is selected from hydrogen, —OCH₃,OCH₂CH₃, —OH, —O(CH)(CH₃)₂, CH₂CH₃, —OCH₂CF₃, and fluoride. In anothersubclass of this subclass, R³ is selected from hydrogen, —OCH₃, andOCH₂CH₃. In another subclass of this subclass, R³ is hydrogen.

In a subclass of this class, R⁴ is selected from the group consistingof: hydrogen, —OH, halogen, —C₁₋₆alkyl optionally substituted withfluoride, and —OC₁₋₆alkyl optionally substituted with fluoride. Inanother subclass of this class, R⁴ is selected from hydrogen, —OCH₃,OCH₂CH₃, —OH, —O(CH)(CH₃)₂, CH₂CH₃, —OCH₂CF₃, and fluoride. In anothersubclass of this subclass, R⁴ is selected from hydrogen, —OCH₃, and—OCH₂CH₃. In another subclass, R⁴ is hydrogen. In another subclass, R⁴is —OCH₃. In another subclass, R⁴ is —OCH₂CH₃.

In another class of the embodiments, R² and R³ are each independentlyselected from the group consisting of: OH, C₁₋₆alkyl, and C₁₋₆alkoxy,wherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents selected from halogen, —OH, C₁₋₆alkyl, and—C₁₋₆alkoxy, or R² and R³ together with the atoms to which they areattached form a 4-8 membered ring containing 0-2 heteroatomsindependently selected from oxygen, sulfur, and N—R¹⁵, wherein the 4-8membered ring is unsubstituted or substituted with a substituentselected from the group consisting of: OH, halogen, C₁₋₆alkyl, andC₁₋₆alkoxy. In another class of the embodiments, R² and R³ are eachindependently selected from the group consisting of: —C₁₋₆alkoxyunsubstituted or substituted with one to five substituents selected fromhalogen, —OH, C₁₋₆alkyl, and —C₁₋₆alkoxy, or R² and R³ together with theatoms to which they are attached form a 4-8 membered ring containing 0-2heteroatoms independently selected from oxygen, sulfur, and N—R¹⁵,wherein the ring is unsubstituted or substituted with a substituentselected from the group consisting of: OH, halogen, C₁₋₆alkyl, andC₁₋₆alkoxy.

In another class of the embodiments, R³ and R⁴ are each independentlyselected from the group consisting of: OH, C₁₋₆alkyl, and C₁₋₆alkoxy,wherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents selected from halogen, OH, C₁₋₆alkyl, and —C₁₋₆alkoxy,or R³ and R⁴ together with the atoms to which they are attached form a4-8 membered ring containing 0-2 heteroatoms independently selected fromoxygen, sulfur, and N—R¹⁵, wherein the 4-8 membered ring isunsubstituted or substituted with a substituent selected from the groupconsisting of: OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy. In another classof the embodiments, R³ and R⁴ are each independently selected from thegroup consisting of: —C₁₋₆alkoxy unsubstituted or substituted with oneto five substituents selected from halogen, —OH, C₁₋₆alkyl, and—C₁₋₆alkoxy, or R³ and R⁴ together with the atoms to which they areattached form a 4-8 membered ring containing 0-2 heteroatomsindependently selected from oxygen, sulfur, and N—R¹⁵, wherein the ringis unsubstituted or substituted with a substituent selected from thegroup consisting of: OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy.

In another class of the embodiments, R¹ and R² are each independentlyselected from the group consisting of: hydrogen, halogen, —OH,—C₁₋₆alkyl, —C₁₋₆alkoxy and —SC₁₋₆-alkyl, wherein alkyl and alkoxy areunsubstituted or substituted with one to five substituents selected fromhalogen, —OH, C₁₋₆alkyl, and C₁₋₆alkoxy, or R³ and R⁴ are eachindependently selected from the group consisting of: —OH, —C₁₋₆alkyl,and —C₁₋₆alkoxy, and alkyl and alkoxy are unsubstituted or substitutedwith one to five substituents selected from halogen, —OH, C₁₋₆alkyl, andC₁₋₆alkoxy, and R³ and R⁴ together with the atoms to which they areattached form a 4-8 membered ring containing 0-2 heteroatomsindependently selected from oxygen, sulfur, and N—R¹⁵, wherein the 4-8membered ring is unsubstituted or substituted with a substituentselected from —OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy; andpharmaceutically acceptable salts thereof. In a subclass of this class,R¹ and R² are hydrogen. In another subclass of this class, R¹ and R² arehydrogen, and R³ and R⁴ form a ring selected from dioxane, piperidine,pyrrolidine, tetrahydropyran, dihydropyran, dihydrofuran,tetrahydrofuran, and dioxolane. In another subclass of this class, R¹and R² are hydrogen, and R³ and R⁴ form a 1,4-dioxane ring, a1,3-dioxolane ring, a tetrahydropyran ring, or a pyrrolidine ring. Inanother subclass of this class, R¹ and R² are hydrogen, and R³ and R³form a 1,4-dioxane ring.

In another class of the embodiments, R¹ and R⁴ are each independentlyselected from the group consisting of: hydrogen, halogen, —OH,—C₁₋₆alkyl, —C₁₋₆alkoxy, and —SC₁₋₆-alkyl, wherein alkyl and alkoxy areunsubstituted or substituted with one to five substituents selected fromhalogen, —OH, C₁₋₆alkyl, and C₁₋₆alkoxy, or R² and R³ are eachindependently selected from the group consisting of: —OH, —C₁₋₆alkyl,and —C₁₋₆alkoxy, and alkyl and alkoxy are unsubstituted or substitutedwith one to five substituents selected from halogen, —OH, C₁₋₆alkyl, andC₁₋₆alkoxy, and R² and R³ together with the atoms to which they areattached form a 4-8 membered ring containing 0-2 heteroatomsindependently selected from oxygen, sulfur, and N—R¹⁵, wherein the 4-8membered ring is unsubstituted or substituted with a substituentselected from —OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy; andpharmaceutically acceptable salts thereof. In a subclass of this class,R¹ and R⁴ are hydrogen. In another subclass of this class, R¹ and R⁴ arehydrogen, and R² and R³ form a ring selected from dioxane, piperidine,pyrrolidine, tetrahydropyran, dihydropyran, dihydrofuran,tetrahydrofuran, and dioxolane. In another subclass of this class, R¹and R⁴ are hydrogen, and R² and R³ form a 1,4-dioxane ring, a1,3-dioxolane ring, a tetrahydropyran ring, or a pyrrolidine ring. Inanother subclass of this class, R¹ and R⁴ are hydrogen, and R² and R³form a 1,4-dioxane ring.

In another class of the embodiments, R⁵, R⁶ and R⁷ are eachindependently selected from the group consisting of: hydrogen, halogen,—OH, —C₁₋₆alkyl, and —C₁₋₆alkoxy, wherein alkyl and alkoxy areunsubstituted or substituted with one to five substituents independentlyselected from halogen, —OH, C₁₋₆alkyl, and C₁₋₆alkoxy.

In a subclass of this class, R⁵ is selected from the group consistingof: hydrogen, —OH, halogen, —C₁₋₆alkyl optionally substituted withfluoride, and —OC₁₋₆alkyl optionally substituted with fluoride. Inanother subclass of this class, R⁵ is selected from hydrogen, —OCH₃,—CH₃, —CH₂CH₃, —CF₃, fluoride and chloride. In another subclass, R⁵ isselected from —C₁₋₆alkyl optionally substituted with fluoride. Inanother subclass, R⁵ is selected from —CH₃. In another subclass, R⁵ ishydrogen.

In another subclass of this class, R⁶ is selected from the groupconsisting of: hydrogen, —OH, halogen, —C₁₋₆alkyl optionally substitutedwith fluoride, and —OC₁₋₆alkyl optionally substituted with fluoride. Inanother subclass of this class, R⁶ is selected from hydrogen, —OCH₃,OCH₂CH₃, —OH, —O(CH)(CH₃)₂, —CH₂CH₃, —OCH₂CF₃, and fluoride. In anothersubclass of this class, R⁶ is selected from hydrogen, —CH₃ and fluoride.In another subclass, R⁶ is hydrogen, —CH₃ and fluoride. In anothersubclass, R⁶ is —CH₃. In another subclass, R⁶ is fluoride. In anothersubclass, R⁶ is hydrogen.

In a subclass of this class, R⁷ is selected from the group consistingof: hydrogen, —OH, halogen, —C₁₋₆alkyl optionally substituted withfluoride, and —OC₁₋₆alkyl optionally substituted with fluoride. In asubclass of this class, R⁷ is selected from hydrogen, and fluoride. Inanother subclass of this class, R⁷ is hydrogen.

In another class of the embodiments, R⁵ is selected from the groupconsisting of: hydrogen, halogen, —OH, —C₁₋₆alkyl, and —C₁₋₆alkoxy,wherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents selected from halogen, —OH, C₁₋₆alkyl, and C₁₋₆alkoxy,and R⁶ and R⁷ are each independently selected from the group consistingof: —OH, —C₁₋₆alkyl, and —C₁₋₆alkoxy, wherein alkyl and alkoxy areunsubstituted or substituted with one to five substituents selected fromhalogen, —OH, C₁₋₆alkyl, and C₁₋₆alkoxy, or R⁶ and R⁷ together with theatoms to which they are attached form a 4-8 membered ring containing 0-2heteroatoms independently selected from oxygen, sulfur, and N—R¹⁵,wherein the 4-8 membered ring is unsubstituted or substituted with asubstituent selected from —OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy; andpharmaceutically acceptable salts thereof. In a subclass of this class,R⁵ is hydrogen. In another subclass of this class, R⁵ is hydrogen, andR⁶ and R⁷ form a ring selected from dioxane, piperidine, pyrrolidine,tetrahydropyran, dihydropyran, dihydrofuran, tetrahydrofuran, anddioxolane. In another subclass of this class, R⁵ is hydrogen, and R⁶ andR⁷ form a 1,4-dioxane ring, a 1,3-dioxolane ring, a tetrahydropyranring, or a pyrrolidine ring. In another subclass of this class, R⁵ ishydrogen, and R⁶ and R⁷ form a 1,4-dioxane ring.

In another class of the embodiments, R⁷ is selected from the groupconsisting of: hydrogen, halogen, —OH, —C₁₋₆alkyl, and —C₁₋₆alkoxy,wherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents selected from halogen, —OH, C₁₋₆alkyl, and C₁₋₆alkoxy,and R⁵ and R⁶ are each independently selected from the group consistingof: —OH, —C₁₋₆alkyl, and —C₁₋₆alkoxy, wherein alkyl and alkoxy areunsubstituted or substituted with one to five substituents selected fromhalogen, —OH, C₁₋₆alkyl, and C₁₋₆alkoxy, or R⁵ and R⁶ together with theatoms to which they are attached form a 4-8 membered ring containing 0-2heteroatoms independently selected from oxygen, sulfur, and N—R¹⁵,wherein the 4-8 membered ring is unsubstituted or substituted with asubstituent selected from —OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy; andpharmaceutically acceptable salts thereof. In a subclass of this class,R⁷ is hydrogen. In another subclass of this class, R⁷ is hydrogen, andR⁵ and R⁶ form a ring selected from dioxane, piperidine, pyrrolidine,tetrahydropyran, dihydropyran, dihydrofuran, tetrahydrofuran, anddioxolane. In another subclass of this class, R⁷ is hydrogen, and R⁵ andR⁶ form a 1,4-dioxane ring, a 1,3-dioxolane ring, a tetrahydropyranring, or a pyrrolidine ring. In another subclass of this class, R⁷ ishydrogen, and R⁵ and R⁶ form a 1,4-dioxane ring.

In another class of the embodiments, R⁵ is independently selected fromthe group consisting of: hydrogen, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, and—C₃₋₆cycloalkyl. In a subclass of this class, R⁸ is hydrogen. In anothersubclass of this class, R⁸ is C₁₋₆alkyl. In another subclass of thisclass, R⁸ is selected from the group consisting of: halogen and —C₁₋₆alkoxy. In a subclass of this subclass, R⁸ is halogen. In anothersubclass of this subclass, R⁸ is selected from the group consisting of:bromide, chloride, fluoride and iodide. In another subclass of thissubclass, R⁸ is bromide.

In another class of the embodiments, each R⁹ is independently selectedfrom the group consisting of: hydrogen, —(CH₂)_(n)CF₃, —(CH₂)_(n)OH,—(CH₂)_(n)CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)C₃₋₈cycloalkyl,—(CH₂)_(n)NR¹¹R¹², -a 5-10 membered aromatic monocyclic or bicyclicheterocyclic ring, phenyl, —C₂₋₆alkene-CO₂R¹², —(CH₂)_(n)C(O)R¹²,—(CH₂)_(n)CO₂R¹², —(CH₂)_(n)OC(O)R¹², —(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹C(O)R¹²,—(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², —(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)NR¹¹CO₂R¹², and —(CH₂)_(n)NR¹¹SO₂R¹², wherein alkyl, alkene,alkoxy, cycloalkyl, the heterocyclic ring, phenyl and —(CH₂)_(n) areunsubstituted or substituted with one to eight substituents selectedfrom oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, phenyl, —(CH₂)_(n)OH,—(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H,—(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene and alkyl and alkoxyare unsubstituted or substituted with one to five substituents selectedfrom halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, provided that atleast one of R⁹ and R¹⁶ is selected from the group consisting of:—C₂₋₆alkene-CO₂R¹², —(CH₂)_(n)C(O)R¹², —(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)OC(O)R¹², —(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹ (CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹C(O)R¹²,—(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², —(CH₂)_(n)NR¹¹CO₂R¹²,—(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹CO₂R¹², and—(CH₂)_(n)NR¹¹SO₂R¹². In a subclass of this class, each R⁹ isindependently selected from the group consisting of: hydrogen,C₂₋₆alkene-CO₂R¹², —(CH₂)_(n)CO₂R¹², —(CH₂)_(n)C(O)R¹²,—(CH₂)_(n)OC(O)R¹², —(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹C(O)R¹²,—(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², —(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹², and—(CH₂)_(n)NR¹¹SO₂R¹², wherein -alkene and (CH₂)_(n) are unsubstituted orsubstituted with one to eight substituents selected from oxo, halogen,—C₁₋₆alkyl, —C₁₋₆alkoxy, phenyl, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, provided that at least one of R⁹ andR¹⁶ is selected from the group consisting of: —C₂₋₆alkene-CO₂R¹²,—(CH₂)_(n)C(O)R¹², —(CH₂)_(n)CO₂R¹², —(CH₂)_(n)OC(O)R¹²,—(CH₂)_(n)O(CH₂)_(n)CO₂R¹², —(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)NR¹¹C(O)R¹², —(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², —(CH₂)_(n)NR¹¹CO₂R¹²,—(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹², and —(CH₂)_(n)NR¹¹SO₂R¹². In anothersubclass of this class, each R⁹ is independently selected from the groupconsisting of: hydrogen, —C₂₋₆alkene-CO₂H, —(CH₂)_(n)CO₂H,—(CH₂)_(n)CO₂C₁₋₆alkyl, —(CH₂)_(n)C(O)C₂₋₈heterocycloalkyl,—CH₂OC(O)C₁₋₆alkyl, —(CH₂)_(n)O(CH₂)_(n)CO₂H,—(CH₂)_(n)O(CH₂)_(n)CO₂C₁₋₆alkyl, —(CH₂)_(n)O(CH₂)_(n)C(O)NHC₁₋₆alkyl,—(CH₂)_(n)C(O)NHC₁₋₈alkyl, —(CH₂)_(n)C(O)N(C₁₋₈alkyl)₂,—(CH₂)_(n)C(O)NHheteroaryl, —(CH₂)_(n)C(O)NHC₃₋₈cycloalkyl,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂H, —(CH₂)_(n)C(O)NH(CH₂)_(n)CO₂C₁₋₆alkyl,—(CH₂)_(n)NHC(O)C₁₋₆alkyl, —(CH₂)_(n)NHC(O)C₃₋₈cycloalkyl,—(CH₂)_(n)NHC(O)aryl, —CH₂NHC(O)NHC₁₋₆alkyl, —(CH₂)_(n)NH(CH₂)_(n)CO₂H,—(CH₂)_(n)NHSO₂C₁₋₆alkyl, —(CH₂)_(n)NHSO₂aryl, and—(CH₂)_(n)NHSO₂C₃—₈cycloalkyl, wherein alkyl, alkene, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, and —(CH₂)_(n) are unsubstituted orsubstituted with one to eight substituents selected from oxo, halogen,—C₁₋₆alkyl, —C₁₋₆alkoxy, phenyl, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, provided that at least one of R⁹ andR¹⁶ is selected from the group consisting of: —C₂₋₆alkene-CO₂R¹²,—(CH₂)_(n)C(O)R¹², —(CH₂)_(n)CO₂R¹², —(CH₂)_(n)OC(O)R¹²,—(CH₂)_(n)O(CH₂)_(n)CO₂R¹², —(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)NR¹¹C(O)R¹², —(CH₂)_(n)NR¹¹C(O)NR¹¹R¹²,—(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹CO₂R¹², and—(CH₂)_(n)NR¹¹SO₂R¹². In a subclass of this subclass, each R⁹ isindependently selected from the group consisting of: hydrogen, —CO₂H,—CH₂CO₂H, —CO₂CH₃, —C(O)piperidine, —C(O)pyrrolidine, —C(O)morpholine,—CH₂OC(O)CH₃, —CH₂OCH₂CO₂H, —CH₂OCH₂C(O)NHCH₃, —CH₂OCH₂C(O)NHCH(CH₃)₂,—C(O)NHCH₃, —C(O)NH(CH₂)₁₋₅CH₃, —C(O)NHCH(CH₃)₂, —CH₂C(O)NHCH(CH₃)₂,—C(O)N(CH₃)₂, —C(O)NHC(CH₃)₃, —C(O)N(CH₂CH₃)₂, —C(O)NH-tetrazole,—C(O)NHCH₂CO₂H, —CH═CHCO₂H, —C(O)NHCH₂CO₂CH(CH₃)₂, —CH₂NHC(O)CH₃,—CH₂NHC(O)cyclopropyl, —CH₂NHC(O)phenyl, —CH₂NHC(O)cyclopentyl,—CH₂NHC(O)NHCH₃, —CH₂NHC(O)NHCH(CH₃)₂, —CH₂NHCH₂CO₂H, —CH₂NHSO₂CH₃, and—CH₂NHSO₂cyclopropyl, wherein the alkyl, alkene, cycloalkyl,heterocycloalkyl, phenyl, and heteroaryl substituents, and —(CH₂)_(n)are unsubstituted or substituted with one to eight substituents selectedfrom oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, phenyl, —(CH₂)_(n)OH,—(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H,—(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene and alkyl and alkoxyare unsubstituted or substituted with one to five substituents selectedfrom halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, provided that atleast one of R⁹ and R¹⁶ is selected from the group consisting of:—C₂₋₆alkene-CO₂R¹², (CH₂)_(n)C(O)R¹², —(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)OC(O)R¹², —(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹C(O)R¹²,—(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², —(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)NR¹¹CO₂R¹², and —(CH₂)_(n)NR¹¹SO₂R¹². In another subclass, oneR⁹ is —CO₂H.

In another class of the embodiments, q is 1 and R⁹ is substituted on thecarbon alpha to the piperazine or piperidine amide nitrogen.

In another class of the embodiments, each R¹⁰ is independently selectedfrom the group consisting of: aryl, and heteroaryl, wherein each aryland heteroaryl ring is unsubstituted or substituted with one to four R¹⁴substituents. In a subclass of this class, R¹⁰ is aryl. In a subclass ofthis subclass, R¹⁰ is selected from phenyl and naphthalene. In anothersubclass of this subclass, R¹⁰ is naphthalene. In another subclass ofthis subclass, R¹⁰ is phenyl. In another subclass of this class, R¹⁰ isheteroaryl. In a subclass of this subclass, R¹⁰ is selected from thegroup consisting of: isoquinoline, benzimidazole, indole, benzothiazole,benzoxazole, quinoline and 1,2,3,4-tetrahydroquinoline. In anothersubclass of this subclass, R¹⁰ is quinoline. In another subclass of thissubclass, R¹⁰ is 1,2,3,4-tetrahydroquinoline.

In a class of the embodiments, each R¹¹, R¹² and R¹³ is independentlyselected from the group consisting of: hydrogen, —C₁₋₈alkyl,—(CH₂)_(n)C₃₋₈cycloalkyl, —(CH₂)_(n)C₂₋₈heterocycloalkyl,—(CH₂)_(n)aryl, and —(CH₂)_(n)heteroaryl, wherein alkyl, cycloalkyl,heterocycloalkyl, and —(CH₂)_(n) are unsubstituted or substituted withone to eight substituents selected from oxo, halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, and wherein aryl and heteroaryl are unsubstituted orsubstituted with one to eight substituents independently selected fromhalogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, or R¹¹ and R¹² together with thenitrogen to which they are attached form a 4-8 membered heterocyclicring containing 0-2 additional heteroatoms selected from oxygen, sulfur,and NR¹⁵, and wherein the 4-8 membered heterocyclic ring isunsubstituted or substituted with one to five substituents independentlyselected from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH,—(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H,—(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl andalkoxy are unsubstituted or substituted with one to five substituentsselected from halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl. In asubclass of this class, R¹¹ is hydrogen. In a subclass of this subclass,R¹¹ is hydrogen and R¹² is independently selected from the groupconsisting of: —C₁₋₆alkyl, —(CH₂)_(n)C₃₋₈cycloalkyl, —(CH₂)_(n)C₂₋₈heterocycloalkyl, —(CH₂)_(n)phenyl, and —(CH₂)_(n)heteroaryl, whereinalkyl, cycloalkyl, heterocycloalkyl, heteroaryl and —(CH₂), areunsubstituted or substituted with one to eight substituents selectedfrom the group consisting of halogen, —(CH₂)_(n)OH, oxo, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)CO₂H,—(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)SO₃H, and alkyl and alkoxy areunsubstituted or substituted with one to five substituents selected fromhalogen, —CO₂H, and —SO₃H. In another subclass of this subclass, R¹¹ ishydrogen and R¹² is independently selected from the group consisting of:hydrogen, —C₁₋₆alkyl, cyclopropyl, morpholine, piperidine, pyrrolidine,and tetrazole.

In another subclass of this class, R¹³ is hydrogen or —C₁₋₆alkyl.

In another class of the embodiments, each R¹⁴ is independently selectedfrom the group consisting of: hydrogen, —(CH₂)_(n)halogen, —(CH₂)_(n)CN,—(CH₂)_(n)NO₂, —(CH₂)_(n)OR¹³, —C₂₋₆alkene-CO₂R¹², —(CH₂)_(n)COR¹³,—(CH₂)_(n)CO₂R¹³, —(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)CONR¹¹COR¹³,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹³, —(CH₂)_(n)C(O)NR¹¹CH(CO₂R¹³)₂,—(CH₂)_(n)NR¹¹R¹², —(CH₂)_(n)NR¹³C(O)NR¹¹R¹², —(CH₂)_(n)NR¹³C(O)R¹³,—(CH₂)_(n)OC(O)NR¹¹R¹², —(CH₂)_(n)NR¹³CO₂R¹³, (CH₂)_(n)NR¹³SO₂R¹³,—(CH₂)_(n)SO₂NR¹¹R¹², —(CH₂)_(n)SO₂R¹³—(CH₂)_(n)SO₃H, —(CH₂)_(n)PO₂R¹³,—(CH₂)_(n)PO₃H, —C₁₋₆alkyl, —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl,—(CH₂)_(n)C₂₋₈heterocycloalkyl, and —(CH₂)_(n)C₃₋₈cycloalkyl, whereinalkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substitutedwith one to five substituents selected from oxo, halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, wherein alkene, aryl and heteroaryl are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein any (CH₂),carbon atom is unsubstituted or substituted with one to two substituentsselected from oxo, halogen, —(CH₂)_(n)OH, —C₁₋₆alkyl, —C₁₋₆alkoxy,—(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H,—(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl andalkoxy are unsubstituted or substituted with one to five substituentsindependently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl. In a subclass of this class, each R¹⁴ is independentlyselected from the group consisting of: hydrogen, —(CH₂)_(n)halogen,—C₂₋₆alkene-CO₂R¹², —(CH₂)_(n)COR¹³, —(CH₂)_(n)CO₂R¹³,—(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)CONHCOR¹³,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹³, —(CH₂)_(n)C(O)NR¹¹CH(CO₂R¹³)₂, and—(CH₂)_(n)heteroaryl, wherein alkene and heteroaryl are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein any (CH₂)_(n)carbon atom is unsubstituted or substituted with one to two substituentsselected from oxo, halogen, —(CH₂)_(n)OH, —C₁₋₆alkyl, —C₁₋₆alkoxy,—(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H,—(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl andalkoxy are unsubstituted or substituted with one to five substituentsindependently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl. In another subclass of this class, each R¹⁴ isindependently selected from the group consisting of: hydrogen,—(CH₂)_(n)halogen, —(CH₂)_(n)COR¹³, —(CH₂)_(n)CO₂R¹³,—(CH₂)_(n)C(O)NR¹¹R¹², and —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹³, whereinany (CH₂)_(n) carbon atom is unsubstituted or substituted with one totwo substituents selected from oxo, halogen, —(CH₂)_(n)OH, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl. In another subclass of this class, each R¹⁴ isindependently selected from the group consisting of: hydrogen, halogen,—C₂₋₆alkene-CO₂H, —C(O)C₂₋₈heterocycloalkyl, —(CH₂)_(n)CO₂H,—CO₂C₁₋₈alkyl, —CO₂CH₂aryl, —CO₂C₂₋₈heterocycloalkyl, —CONH₂,—CONHC₁₋₆alkyl, —CON(C₁₋₆alkyl)₂, —C(O)NHC₃₋₈cycloalkyl, —CONHaryl,—C(O)NH(CH₂)_(n)OH, —C(O)NHC₂₋₈heterocycloalkyl, —C(O)NHCH₂CO₂H,—C(O)N(C₁₋₆alkyl)CH₂CO₂H, —CONHCOC₁₋₆alkyl, —C(O)NHCH(CO₂CH₂aryl)₂,—C(O)NHCH(CO₂C₁₋₆alkyl)₂, and -heteroaryl, wherein alkyl, cycloalkyl,and heterocycloalkyl are unsubstituted or substituted with one to fivesubstituents selected from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy,—(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene,wherein alkene, aryl, and heteroaryl are unsubstituted or substitutedwith one to five substituents independently selected from halogen,—C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃,—(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and—(CH₂)_(n)CO₂C₂₋₆alkene, and wherein any (CH₂)_(n)carbon atom isunsubstituted or substituted with one to two substituents selected fromoxo, halogen, —(CH₂)_(n)OH, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl. In another subclass ofthis class, each R¹⁴ is independently selected from the group consistingof: hydrogen, halogen, —C(O)C₂₋₈heterocycloalkyl, —(CH₂)_(n)CO₂H,—CONH₂, —CONHC₁₋₆alkyl, —CON(C₁₋₆alkyl)₂, —C(O)NHC₃₋₈cycloalkyl,—CONHaryl, —C(O)NHCH₂CO₂H, and —C(O)N(C₁₋₆alkyl)CH₂CO₂H, wherein alkyl,cycloalkyl, and heterocycloalkyl are unsubstituted or substituted withone to five substituents selected from oxo, halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, (CH₂)_(n)CN, (CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene,wherein aryl is unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andwherein any (CH₂)_(n) carbon atom is unsubstituted or substituted withone to two substituents selected from oxo, halogen, —(CH₂)_(n)OH,—C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl.

In another subclass of this class, each R¹⁴ is independently selectedfrom the group consisting of: hydrogen, Cl, —CH═CHCO₂H, —C(O)morpholine,—C(O)pyrrolidine, —C(O)piperidine, —CO₂H, —CO₂CH₂phenyl, —CO₂CH₃,—(CH₂)₂CO₂H, —CO₂tetrahydropyran, —CONHCH₃, —CONHCH₂CH₃, —CON(CH₂CH₃)₂,—CON(CH₃)₂, —CONHCH(CH₃)₂, —CONHcyclopropyl, —CONHphenyl,—C(O)NHcyclopentyl, —C(O)NH(CH₂)₁₋₆OH, —C(O)NHtetrahydropyran,—CONHCH₂CO₂H, —CON(CH₃)CH₂CO₂H, —CONHCOC(CH₃)₃,—C(O)NHCH(CO₂CH₂phenyl)₂, —C(O)NHCH(CO₂CH₂CH₃)₂, and tetrazole, whereinthe alkyl, cycloalkyl, and heterocycloalkyl substituents areunsubstituted or substituted with one to five substituents selected fromoxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, wherein the alkene, aryl, and heteroarylsubstituents are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andwherein any (CH₂)_(n) carbon atom is unsubstituted or substituted withone to two substituents selected from oxo, halogen, —(CH₂)_(n)OH,—C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl. In another subclass of this class, each R¹⁴ isindependently selected from the group consisting of: hydrogen,—C(O)morpholine, —C(O)pyrrolidine, —CO₂H, —CONHCH₃, —CONHCH₂CH₃,—CON(CH₂CH₃)₂, —CON(CH₃)₂, —CONHCH(CH₃)₂, —CONHcyclopropyl, —CONHphenyl,—CONHCH₂CO₂H, and —CON(CH₃)CH₂CO₂H, wherein the alkyl, cycloalkyl, andheterocycloalkyl substituents are unsubstituted or substituted with oneto five substituents selected from oxo, halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene,wherein the phenyl substituent is unsubstituted or substituted with oneto five substituents independently selected from halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andwherein any (CH₂)_(n) carbon atom is unsubstituted or substituted withone to two substituents selected from oxo, halogen, —(CH₂)_(n)OH,—C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy substituents are unsubstituted or substituted with oneto five substituents independently selected from halogen, —OH, —SO₃H,—CO₂H, and —CO₂C₁₋₆alkyl. In another subclass, one R¹⁴ is —CO₂H. Inanother subclass, R¹⁴ is hydrogen.

In another class of the embodiments, each R¹⁵ is independently selectedfrom the group consisting of: hydrogen, —C₁₋₆alkyl, —C₃₋₈cycloalkyl,—SO₂R¹², —COR¹³, and —CO₂R¹², wherein alkyl and cycloalkyl areunsubstituted or substituted with one to six substituents selected fromhalogen, —OH, and —(CH₂)_(n)CO₂H.

In another class of the embodiments, each R¹⁶ is independently selectedfrom the group consisting of: hydrogen, —(CH₂)_(n)CF₃, —(CH₂)_(n)OH,—(CH₂)_(n)CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)C₃₋₈cycloalkyl,—(CH₂)_(n)NR¹¹R¹², -a 5-10 membered aromatic monocyclic or bicyclicheterocyclic ring, phenyl, —C₂₋₆alkene-CO₂R¹², —(CH₂)_(n)C(O)R¹²,—(CH₂)_(n)CO₂R¹², —(CH₂)_(n)OC(O)R¹², —(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹C(O)R¹²,—(CH₂)_(n)NR¹¹C(O)NR¹¹R¹²,—(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹²—(CH₂)_(n)NR¹¹CO₂R¹², and—(CH₂)_(n)NR¹¹SO₂R¹², wherein alkyl, alkene, alkoxy,—(CH₂)_(n)cycloalkyl, the heterocyclic ring and phenyl are unsubstitutedor substituted with one or more substituents selected from C₁₋₆alkyl,—OH, C₁₋₆alkoxy, —CF₃, —CN, phenyl and halogen, provided that at leastone of R⁹ and R¹⁶ is selected from the group consisting of:—C₂₋₆alkene-CO₂R¹², —(CH₂)_(n)C(O)R¹², —(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)OC(O)R¹², —(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹C(O)R¹²,—(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², —(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)NR¹¹CO₂R¹², and —(CH₂)_(n)NR¹¹SO₂R¹². In a subclass of thisclass, each R¹⁶ is independently selected from the group consisting of:hydrogen, —C₂₋₆alkene-CO₂R¹², —(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)O(CH₂)_(n)CO₂R¹², —(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹C(O)R¹², and—(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², wherein alkene and —(CH₂)_(n) areunsubstituted or substituted with one or more substituents selected fromC₁₋₆alkyl, —OH, C₁₋₆alkoxy, —CF₃, —CN, phenyl and halogen, provided thatat least one of R⁹ and R¹⁶ is selected from the group consisting of:—C₂₋₆alkene-CO₂R¹², —(CH₂)_(n)C(O)R¹², —(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)OC(O)R¹²—(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹C(O)R¹²,—(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², —(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)NR¹¹CO₂R¹², and —(CH₂)NR¹¹SO₂R¹². In another subclass of thisclass, each R¹⁶ is independently selected from the group consisting of:hydrogen, —CH═CHCO₂H, —CO₂H, —CH₂CO₂H, —(CH₂)₂CO₂H, —OCH₂CO₂H,—OCH₂CO₂C(CH₂)₃, —CONHCH₃, —CON(CH₃)₂, —CONH₂, —CONHCH₃, —CONHCH₃,—CONHCH₃, —CONHCH₂CO₂H, —NHCOCH₃, and —NHCONHCH₃, wherein alkyl and—(CH₂)_(n), are unsubstituted or substituted with one or moresubstituents selected from C₁₋₆alkyl, —OH, C₁₋₆alkoxy, —CF₃, —CN, phenyland halogen, provided that at least one of R⁹ and R¹⁶ is selected fromthe group consisting of: —C₂₋₆alkene-CO₂R¹², —(CH₂)_(n)C(O)R¹²,—(CH₂)_(n)CO₂R¹², —(CH₂)_(n)OC(O)R¹², —(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², (CH₂)_(n)NR¹¹C(O)R¹¹,—(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², —(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)NR¹¹CO₂R¹², and —(CH₂)_(n)NR¹¹SO₂R¹². In yet another subclassof this class, each R¹⁶ is independently selected from the groupconsisting of: hydrogen, —CO₂H, —CH₂CO₂H, —(CH₂)₂CO₂H, —OCH₂CO₂H,—CONHCH₃, —CON(CH₃)₂, —CONH₂, —CONHCH₂CO₂H, —NHCOCH₃, and —NHCONHCH₃,wherein alkyl and —(CH₂)_(n), are unsubstituted or substituted with oneor more substituents selected from C₁₋₆alkyl, —OH, C₁₋₆alkoxy, —CF₃,—CN, phenyl and halogen, provided that at least one of R⁹ and R¹⁶ isselected from the group consisting of: —C₂₋₆alkene-CO₂R¹²,—(CH₂)_(n)C(O)R¹², —(CH₂)_(n)CO₂R¹², —(CH₂)_(n)OC(O)R¹²,—(CH₂)_(n)O(CH₂)_(n)CO₂R¹², (CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)NR¹¹C(O)R¹², —(CH₂)_(n)NR¹¹C(O)NR¹¹R¹²,—(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹CO₂R¹², and—(CH₂)_(n)NR¹¹SO₂R¹².

In another class of the embodiments, each m is independently 0, 1, 2, 3or 4. In a subclass of this class, m is 0, 1, or 2. In another subclassof this class, m is 0. In another subclass of this class, m is 1. Inanother subclass of this class, m is 2.

In another class of the embodiments, each n is independently 0, 1, 2, 3,4, 5, 6, 7 or 8. In a subclass of this class, each n is independently 0,1, 2, 3, 4, 5 or 6. In a subclass of this class, n is 0, 1, or 2. Inanother subclass of this class, n is 0. In another subclass of thisclass, n is 1. In another subclass of this class, n is 2. In anothersubclass of this class, n is 3. In another subclass of this class, n is4. In another subclass of this class, n is 5. In another subclass ofthis class, n is 6.

In another class of the embodiments, each p is independently 0, 1, 2, or3. In a subclass of this class, p is 1, 2 or 3. In another subclass ofthis class, p is 1. In another subclass of this class, p is 2. Inanother subclass of this class, p is 3.

In another class of the embodiments, each q is independently 0, 1, 2, 3or 4. In a subclass of this class, q is 1, 2 or 3. In another subclassof this class, q is 1. In another subclass of this class, q is 2. Inanother subclass of this class, q is 3.

In another class of the embodiments, R¹⁰ is naphthalene, m is 1 and p is0.

In another class of the embodiments, R¹⁰ is quinoline, m is 0 and p is0.

In another embodiment, the compound of formula I is selected from:

-   (1)    3-{(3S)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoic    acid,-   (2)    3-{(3S)-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoic    acid,-   (3)    3-((3R)-3-[(acetylamino)methyl]-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic    acid,-   (4)    3-[1-{[1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperidin-4-yl]propanoic    acid,-   (5)    (2S)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(3-quinolinyl)-2-piperazinecarboxylic    acid, trifluoroacetic acid salt,-   (6)    (2S)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(3-quinolinyl)-2-ethyl-4-(3-quinolinyl)-2-piperazinecarboxamide,    trifluoroacetic acid salt,-   (7)    N-{[(2S)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]car    bonyl}-4-(3-quinolinyl)-2-piperazinyl]carbonyl}glycine,-   (8)    {[(2S)-1-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(3-quinolinyl)-2-piperazinyl]methoxy}acetic    acid,-   (9)    3-((3R)-4-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-{[2-(methylamino)-2-oxoethoxy]methyl}-1-piperazinyl)-1-naphthoic    acid,-   (10)    3-((3R)-4-([1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-{[2-(methylamino)-2-oxoethoxy]methyl}-1-piperazinyl)-1-naphthoic    acid, and-   (11)    (2S)-4-(4-Carboxy-2-naphthyl)-1-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-2-piperazinecarboxylic    acid;    or a pharmaceutically acceptable salt thereof.

In a class of this embodiment, the compound of formula I is selectedfrom:

-   (1)    3-{(3S)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoic    acid,-   (2)    3-{(3S)-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoic    acid,-   (3)    3-((3R)-3-[(acetylamino)methyl]-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic    acid, and-   (4)    3-[1-{[1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperidin-4-yl]propanoic    acid;    or a pharmaceutically acceptable salt thereof.

In a subclass of this class, the compound of formula I is selected from:3-{(3S)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoicacid; or a pharmaceutically acceptable salt thereof. In another subclassof this class, the compound of formula I is selected from3-{(3S)-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoicacid; or a pharmaceutically acceptable salt thereof. In another subclassof this class, the compound of formula I is selected from3-((3R)-3-[(acetylamino)methyl]-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; or a pharmaceutically acceptable salt thereof. In another subclassof this class, the compound of formula I is selected from3-[1-{[1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperidin-4-yl]propanoicacid; or a pharmaceutically acceptable salt thereof.

In another class of the embodiments, the pharmaceutically acceptablesalt is a trifluoroacetic acid salt. In another class of theembodiments, the pharmaceutically acceptable salt is a hydrochloric acidsalt.

The compounds of formula I, II III and IV are effective ascholecystokinin receptor ligands and are particularly effective asselective ligands of the cholecystokinin-1 receptor. They are thereforeuseful for the treatment and/or prevention of disorders responsive tothe modulation of the cholecystokinin-1 receptor, such as obesity,diabetes, and obesity-related disorders. More particularly, thecompounds of formula I, II, III and IV are selective cholecystokinin-1receptor (CCK-1R) agonists useful for the treatment of disordersresponsive to the activation of the cholecystokinin-1 receptor, such asobesity, diabetes, as well as the treatment of gallstones.

One aspect of the present invention provides a method for the treatmentor prevention of disorders, diseases or conditions responsive to themodulation of the cholecystokinin-1 receptor in a subject in needthereof which comprises administering to the subject a therapeuticallyor prophylactically effective amount of a compound of formula I, II, IIIor IV, or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a method for thetreatment or prevention of obesity, diabetes, or an obesity relateddisorder in a subject in need thereof which comprises administering tosaid subject a therapeutically or prophylactically effective amount of acholecystokinin-1 receptor agonist of the present invention. Anotheraspect of the present invention provides a method for the treatment orprevention of obesity in a subject in need thereof which comprisesadministering to the subject a therapeutically or prophylacticallyeffective amount of a compound of formula I, II, III or IV, or apharmaceutically acceptable salt thereof. Another aspect of the presentinvention provides a method for reducing food intake in a subject inneed thereof which comprises administering to the subject atherapeutically or prophylactically effective amount of a compound offormula I, II, III or IV, or a pharmaceutically acceptable salt thereof.Another aspect of the present invention provides a method for increasingsatiety in a subject in need thereof which comprises administering tothe subject a therapeutically or prophylactically effective amount of acompound of formula I, II, III or IV, or a pharmaceutically acceptablesalt thereof. Another aspect of the present invention provides a methodfor reducing appetite in a subject in need thereof which comprisesadministering to the subject a therapeutically or prophylacticallyeffective amount of a compound of formula I, II, III or IV, or apharmaceutically acceptable salt thereof. Another aspect of the presentinvention provides a method for reducing gastric emptying in a subjectin need thereof which comprises administering to the subject atherapeutically or prophylactically effective amount of a compound offormula I, II, III or IV, or a pharmaceutically acceptable salt thereof.Another aspect of the present invention provides a method for thetreatment or prevention of bulimia nervosa in a subject in need thereofwhich comprises administering to the subject a therapeutically orprophylactically effective amount of a compound of formula I, II, III orIV, or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a method for thetreatment or prevention of diabetes mellitus in a subject in needthereof comprising administering to the subject a therapeutically orprophylactically effective amount of a compound of formula I, II, III orIV, or a pharmaceutically acceptable salt thereof. Another aspect of thepresent invention provides a method for the treatment or prevention ofdyslipidemia in a subject in need thereof which comprises administeringto the subject a therapeutically or prophylactically effective amount ofa compound of formula I, II, III or IV, or a pharmaceutically acceptablesalt thereof. Another aspect of the present invention provides a methodfor the treatment or prevention of tardive dyskinesia in a subject inneed thereof which comprises administering to said subject atherapeutically or prophylactically effective amount of acholecystokinin-1 receptor agonist of the present invention.

Another aspect of the present invention provides a method for thetreatment or prevention of an obesity-related disorder selected from thegroup consisting of overeating, binge eating, hypertension, elevatedplasma insulin concentrations, insulin resistance, hyperlipidemia,endometrial cancer, breast cancer, prostate cancer, colon cancer, kidneycancer, osteoarthritis, obstructive sleep apnea, heart disease, abnormalheart rhythms and arrythmias, myocardial infarction, congestive heartfailure, coronary heart disease, sudden death, stroke, polycystic ovarydisease, craniopharyngioma, metabolic syndrome, insulin resistancesyndrome, sexual and reproductive dysfunction, infertility,hypogonadism, hirsutism, obesity-related gastro-esophageal reflux,Pickwickian syndrome, inflammation, systemic inflammation of thevasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia,lower back pain, gallbladder disease, gout, constipation, irritablebowel syndrome, inflammatory bowel syndrome, cardiac hypertrophy, leftventricular hypertrophy, in a subject in need thereof which comprisesadministering to the subject a therapeutically or prophylacticallyeffective amount of a compound of formula I, II, III or IV, or apharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a method for thetreatment or prevention of cognitive and memory deficiency, includingthe treatment of Alzheimer's disease, in a subject in need thereof whichcomprises administering to the subject a therapeutically orprophylactically effective amount of a compound of formula I, II, III orIV, or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a method for thetreatment or prevention of pain in a subject in need thereof whichcomprises administering to the subject a therapeutically orprophylactically effective amount of a compound of formula I, II, III orIV, or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a method for thetreatment or prevention of cholelithiasis (gallstones) in a subject inneed thereof which comprises administering to the subject atherapeutically or prophylactically effective amount of a compound offormula I, II, III or IV, or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a method for thetreatment or prevention of cholecystitis (inflammation of thegallbladder) in a subject in need thereof which comprises administeringto the subject a therapeutically or prophylactically effective amount ofa compound of formula I, II, III or IV, or a pharmaceutically acceptablesalt thereof.

The present invention also relates to methods for treating or preventingobesity by administering a cholecystokinin-1 receptor agonist of thepresent invention in combination with a therapeutically orprophylactically effective amount of another agent known to be useful totreat or prevent the condition. The present invention also relates tomethods for treating or preventing diabetes by administering thecholecystokinin-1 receptor agonist of the present invention incombination with a therapeutically or prophylactically effective amountof another agent known to be useful to treat or prevent the condition.The present invention also relates to methods for treating or preventingobesity related disorders by administering the cholecystokinin-1receptor agonist of the present invention in combination with atherapeutically or prophylactically effective amount of another agentknown to be useful to treat or prevent the condition.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of formula I, II, III or IV and apharmaceutically acceptable carrier.

Yet another aspect of the present invention relates to the use of acompound of formula I, II, III, or IV for the manufacture of amedicament useful for the treatment or prevention, or suppression of adisease mediated by the cholecystokinin-1 receptor in a subject in needthereof. Yet another aspect of the present invention relates to the useof a cholecystokinin-1 agonist of the present invention for themanufacture of a medicament useful for the treatment or prevention, orsuppression of a disease mediated by the cholecystokinin-1 receptor,wherein the disease is selected from the group consisting of obesity,diabetes and an obesity-related disorder in a subject in need thereof.

Yet another aspect of the present invention relates to the use of acholecystokinin-1 agonist of the present invention for the manufactureof a medicament useful for the treatment or prevention of gallstones ina subject in need thereof. Yet another aspect of the present inventionrelates to the use of a cholecystokinin-1 agonist of the presentinvention for the manufacture of a medicament useful for the treatmentor prevention of dyslipidemia in a subject in need thereof. Yet anotheraspect of the present invention relates to the use of acholecystokinin-1 agonist of the present invention for the manufactureof a medicament useful for the treatment or prevention of bulimianervosa in a subject in need thereof. Yet another aspect of the presentinvention relates to the use of a cholecystokinin-1 agonist of thepresent invention for the manufacture of a medicament useful for thetreatment or prevention of constipation in a subject in need thereof.Yet another aspect of the present invention relates to the use of acholecystokinin-1 agonist of the present invention for the manufactureof a medicament useful for the treatment or prevention of irritablebowel syndrome in a subject in need thereof.

Yet another aspect of the present invention relates to the use of atherapeutically effective amount of a cholecystokinin-1 receptor agonistof formula I, II, III or IV, or a pharmaceutically acceptable saltthereof, and a therapeutically effective amount of an agent selectedfrom the group consisting of an insulin sensitizer, an insulin mimetic,a sulfonylurea, an α-glucosidase inhibitor, a dipeptidyl peptidase 4(DPP-4 or DP-IV) inhibitor, a glucagons like peptide 1 (GLP-1) agonist,a HMG-CoA reductase inhibitor, a serotonergic agent, a β3-adrenoreceptoragonist, a neuropeptide Y1 antagonist, a neuropeptide Y2 agonist, aneuropeptide Y5 antagonist, a pancreatic lipase inhibitor, a cannabinoidCB₁ receptor antagonist or inverse agonist, a melanin-concentratinghormone receptor antagonist, a melanocortin 4 receptor agonist, abombesin receptor subtype 3 agonist, a ghrelin receptor antagonist, PYY,PYY₃₋₃₆, and a NK-1 antagonist, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament useful for the treatment,control, or prevention of obesity, diabetes or an obesity-relateddisorder in a subject in need of such treatment. Yet another aspect ofthe present invention relates to the use of a therapeutically effectiveamount of a cholecystokinin-1 receptor agonist of formula I, II, III, orIV, and pharmaceutically acceptable salts and esters thereof, and atherapeutically effective amount of an agent selected from the groupconsisting of an insulin sensitizer, an insulin mimetic, a sulfonylurea,an α-glucosidase inhibitor, a dipeptydyl peptidase 4 inhibitor, aglucagon-like peptide 1 agonist, a HMG-CoA reductase inhibitor, aserotonergic agent, a β3-adrenoreceptor agonist, a neuropeptide Y1antagonist, a neuropeptide Y2 agonist, a neuropeptide Y5 antagonist, apancreatic lipase inhibitor, a cannabinoid CB₁ receptor antagonist orinverse agonist, a melanin-concentrating hormone receptor antagonist, amelanocortin 4 receptor agonist, a bombesin receptor subtype 3 agonist,a ghrelin receptor antagonist, PYY, PYY3-36, and a NK-1 antagonist, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for treatment or prevention of obesity, diabetes or anobesity-related disorder which comprises an effective amount of acholecystokinin-1 receptor agonist of formula I, II, III, or IV and aneffective amount of the agent, together or separately. Yet anotheraspect of the present invention relates to a product containing atherapeutically effective amount of a cholecystokinin-1 receptor agonistof formula I, II, III, or IV, or a pharmaceutically acceptable saltthereof; and a therapeutically effective amount of an agent selectedfrom the group consisting of an insulin sensitizer, an insulin mimetic,a sulfonylurea, an α-glucosidase inhibitor, a HMG-CoA reductaseinhibitor, a serotonergic agent, a β3-adrenoreceptor agonist, aneuropeptide Y1 antagonist, a neuropeptide Y2 agonist, a neuropeptide Y5antagonist, a pancreatic lipase inhibitor, a cannabinoid CB₁ receptorantagonist or inverse agonist, a melanocortin 4 receptor agonist, amelanin-concentrating hormone receptor antagonist, a bombesin receptorsubtype 3 agonist, a ghrelin receptor antagonist, PYY, PYY3-36, and aNK-1 antagonist, or a pharmaceutically acceptable salt thereof, as acombined preparation for simultaneous, separate or sequential use inobesity, diabetes, or an obesity-related disorder.

The compounds of formula I, II, III and IV can be provided in kit. Sucha kit typically contains an active compound in dosage forms foradministration. A dosage form contains a sufficient amount of activecompound such that a beneficial effect can be obtained when administeredto a patient during regular intervals, such as 1, 2, 3, 4, 5 or 6 timesa day, during the course of 1 or more days. Preferably, a kit containsinstructions indicating the use of the dosage form for weight reduction(e.g., to treat obesity) and the amount of dosage form to be taken overa specified time period.

Throughout the instant application, the following terms have theindicated meanings:

The term “alkyl”, as well as other groups and substituents having theprefix “alk”, such as alkoxy, alkanoyl, means carbon chains of thedesignated length which may be in a straight or branched configuration,or combinations thereof. Examples of alkyl groups and substituentsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl,2-methylpropyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl,2,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethyl butyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethyl butyl, n-heptyl,1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl,5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl,4-ethylpentyl, 1-propylbutyl, 2-propylbutyl, 3-propylbutyl,1,1-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl,1,4-dimethylpentyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl.2,4-dimethylpentyl, 3,3-dimethylpentyl, 3,4-dimethylpentyl,4,4-dimethylpentyl, 1-methyl-1-ethylbutyl, 1-methyl-2-ethylbutyl,2-methyl-2-ethylbutyl, 1-ethyl-2-methylbutyl, 1-ethyl-3-methylbutyl,1,1-diethylpropyl, n-octyl, n-nonyl, and the like.

The term “alkenyl” means carbon chains which contain at least onecarbon-carbon double bond, and which may be linear or branched orcombinations thereof. Examples of alkenyl include vinyl, allyl,isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, and the like.

The term “alkynyl” means carbon chains which contain at least onecarbon-carbon triple bond, and which may be linear or branched orcombinations thereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl and the like.

The term “alkoxy” means alkyl chains of the designated length whichcontain at least one ether linkage and which may be linear or branchedor combinations thereof. Examples of alkoxy include methoxy, ethoxy,1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, methylmethoxy, methylethoxy,methyl-1-propoxy, methyl-2-propoxy, ethyl-2-methoxy, ethyl-1-methoxy andthe like.

The term “halogen” includes fluorine, chlorine, bromine and iodine.

The term “C₁₋₄ alkyliminoyl” means C₁₋₃C(═NH)—.

The term “aryl” includes mono- or bicyclic aromatic rings containingonly carbon atoms in which at least one ring is aromatic. Examples ofaryl include phenyl and naphthalene.

The term “heteroaryl” includes mono- and bicyclic aromatic ringscontaining from 1 to 4 heteroatoms selected from nitrogen, oxygen andsulfur, in which at least one ring is aromatic. Examples thereofinclude, but are not limited to, pyridinyl, furyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, triazolyl, triazinyl, tetrazolyl, thiadiazolyl,imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyrazolyl,pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl,benzimidazolyl, benzofuryl, benzothienyl, indolyl, benzthiazolyl,benzoxazolyl, and the like. In one embodiment of the present invention,heteroaryl is selected from the group consisting of pyridinyl, furyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, triazolyl, triazinyl,tetrazolyl, thiadiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxathiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl,quinolyl, isoquinolyl, benzimidazolyl, benzofuryl, benzothienyl,indolyl, benzthiazolyl, and benzoxazolyl. Bicyclic heteroaromatic ringsinclude, but are not limited to, benzothiadiazole, indole,benzothiophene, benzofuran, benzimidazole, benzisoxazole, benzothiazole,quinoline, quinazoline, benzotriazole, benzoxazole, isoquinoline,purine, furopyridine, thienopyridine, benzisodiazole,triazolopyrimidine, 1,2,3,4-tetrahydroquinoline, and5,6,7,8-tetrahydroquinoline.

The term “cycloalkyl” includes mono- or bicyclic non-aromatic ringscontaining only carbon atoms. Examples of cycloalkyl include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl.

The term “heterocycloalkyl” is intended to include non-aromaticheterocycles containing one to four heteroatoms selected from nitrogen,oxygen and sulfur. Examples of heterocycloalkyls include, but are notlimited to, azetidine, piperidine, morpholine, thiamorpholine,pyrrolidine, imidazolidine, tetrahydrofuran, tetrahydropyran,piperazine, 1-thia-4-aza-cyclohexane.

The term “5-10 membered aromatic monocyclic or bicyclic heterocyclicring” means a 5- or 6-membered aromatic heterocyclic ring or a fusedbicyclic aromatic ring, which may contain one to three of theheteroatoms selected from nitrogen, oxygen and sulfur, and includes, butis not limited to, furyl, thienyl, isoxazolyl, pyridyl, pyrimidinyl,benzofuranyl, and benzothienyl.

Certain of the above defined terms may occur more than once in the aboveformula and upon such occurrence each term shall be definedindependently of the other; thus for example, NR⁴R⁴ may represent NH₂,NHCH₃, N(CH₃)CH₂CH₃, and the like.

The term “subject” means a mammal. One embodiment of the term “mammal”is a “human,” said human being either male or female. The instantcompounds are also useful for treating or preventing obesity and obesityrelated disorders in cats and dogs. As such, the term “mammal” includescompanion animals such as cats and dogs. The term “mammal in needthereof” refers to a mammal who is in need of treatment or prophylaxisas determined by a researcher, veterinarian, medical doctor or otherclinician.

The term “composition”, as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

By a cholecystokinin receptor “agonist” is meant an endogenous or drugsubstance or compound that can interact with a cholecystokinin receptorand initiate a pharmacological or biochemical response characteristic ofcholecystokinin receptor activation. The “agonistic” properties of thecompounds of the present invention were measured in the functional assaydescribed below.

By “binding affinity” is meant the ability of a compound/drug to bind toits biological target, in the present instance, the ability of acompound of formula I, II, III, or IV, to bind to a cholecystokininreceptor. Binding affinities for the compounds of the present inventionwere measured in the binding assay described below and are expressed asIC₅₀'s.

“Efficacy” describes the relative intensity of response which differentagonists produce even when they occupy the same number of receptors andwith the same affinity. Efficacy is the property that describes themagnitude of response. Properties of compounds can be categorized intotwo groups, those which cause them to associate with the receptors(binding affinity) and those that produce a stimulus (efficacy). Theterm “efficacy” is used to characterize the level of maximal responsesinduced by agonists. Not all agonists of a receptor are capable ofinducing identical levels of maximal responses. Maximal response dependson the efficiency of receptor coupling, that is, from the cascade ofevents, which, from the binding of the drug to the receptor, leads tothe desired biological effect.

The functional activities expressed as EC₅₀'s and the “agonist efficacy”for the compounds of the present invention at a particular concentrationwere measured in the functional assay described below. The CCK1R activeand selective agonists of the present invention have an IC₅₀≦500 nM,preferably IC₅₀<100 nM, more preferably IC₅₀<10 nM, and most preferablyIC₅₀<1 nM, while having at least 100-fold and preferably greater than1000-fold selectivity over CCK2R. The CCK1R active and selectiveagonists of the present invention have an EC₅₀≦500 nM, preferablyEC₅₀<100 nM, more preferably EC₅₀<10 nM, and most preferably EC₅₀<1 nM,while having at least 100-fold, and preferably greater than 1000-foldselectivity over CCK2R.

Compounds of formula I, II, III, and IV may contain one or moreasymmetric or chiral centers and can exist in different stereoisomericforms, such as racemates and racemic mixtures, single enantiomers,enantiomeric mixtures, individual diastereomers and diastereomericmixtures. All stereoisomeric forms of the intermediates and compounds ofthe present invention as well as mixtures thereof, including racemic anddiastereomeric mixtures, which possess properties useful in thetreatment of the conditions discussed herein or are intermediates usefulin the preparation of compounds having such properties, form a part ofthe present invention.

Generally, one of the enantiomers will be more active biologically thanthe other enantiomer. Racemic mixtures can subsequently be separatedinto each enantiomer using standard conditions, such as resolution orchiral chromatography. Diastereomeric mixtures may be separated intotheir individual diastereoisomers on the basis of their physicalchemical differences by methods well known to those skilled in the art,such as by chiral chromatography using an optically active stationaryphase and/or fractional crystallization from a suitable solvent.Absolute stereochemistry may be determined by X-ray crystallography ofcrystalline products or crystalline intermediates which are derivatized,if necessary, with a reagent containing an asymmetric center of knownabsolute configuration. Enantiomers may be separated by use of a chiralHPLC column and by converting the enantiomeric mixture into adiastereomeric mixture by reaction with an appropriate optically activecompound (e.g., chiral auxiliary such as a chiral alcohol or Mosher'sacid chloride), separating the diastereoisomers and converting (e.g.,hydrolyzing) the individual diastereoisomers to the corresponding pureenantiomers. Alternatively, any stereoisomer of a compound of thegeneral formula I, II, III, and IV may be obtained by stereospecificsynthesis using optically pure starting materials or reagents of knownabsolute configuration.

The present invention includes all such isomeric forms of the compoundsof formula I, II, III, and IV, including the E and Z geometric isomersof double bonds and mixtures thereof. A number of the compounds of thepresent invention and intermediates therefor exhibit tautomerism andtherefore may exist in different tautomeric forms under certainconditions. The term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. A specificexample of a proton tautomer is an imidazole moiety where the hydrogenmay migrate between the ring nitrogens. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons. Allsuch tautomeric forms (e.g., all keto-enol and imine-enamine forms) arewithin the scope of the invention. The depiction of any particulartautomeric form in any of the structural formulas herein is not intendedto be limiting with respect to that form, but is meant to berepresentative of the entire tautomeric set.

The present invention also encompasses isotopically labeled compoundswhich are identical to the compounds of Formula (I) or intermediatesthereof but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into the intermediates or compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C,13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 123I, 125I and 36Cl,respectively. Compounds of the present invention, prodrugs thereof andpharmaceutically acceptable salts, hydrates and solvates of saidcompounds and of said prodrugs which contain the aforementioned isotopesand/or other isotopes of other atoms are within the scope of the presentinvention. Certain isotopically labeled compounds of the presentinvention (e.g., those labeled with 3H and 14C) are useful in compoundand/or substrate tissue distribution assays. Tritiated (i.e., 3H) andcarbon-14 (i.e., 14C) isotopes are particularly preferred for their easeof preparation and detectability. Further, substitution with heavierisotopes such as deuterium (i.e., 2H) may afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements) and hence may bepreferred in some circumstances. Positron emitting isotopes such as 15O,13N, 11C, and 18F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds of the present invention can generally be prepared byfollowing procedures analogous to those disclosed in the Schemes and/orin the Examples herein by substituting an isotopically labeled reagentfor a non-isotopically labeled reagent.

The compounds of the present invention and intermediates may exist inunsolvated as well as solvated forms with solvents such as water,ethanol, isopropanol and the like, and both solvated and unsolvatedforms are included within the scope of the invention. Solvates for usein the methods aspect of the invention should be with pharmaceuticallyacceptable solvents. It will be understood that the compounds of thepresent invention include hydrates, solvates, polymorphs, crystalline,hydrated crystalline and amorphous forms of the compounds of the presentinvention, and pharmaceutically acceptable salts thereof.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, lithium, magnesium, potassium, and sodium salts.Salts derived from pharmaceutically acceptable organic non-toxic basesinclude salts of primary, secondary, and tertiary amines, substitutedamines including naturally occurring substituted amines, cyclic amines,and basic ion exchange resins, such as arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, TEA, trimethylamine, tripropylamine,tromethamine, and the like.

When the compound of formula I, II, III and IV is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric,gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric,pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric,tartaric, p-toluenesulfonic acid, trifluoroacetic acid, and the like.Particularly preferred are citric, fumaric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids. It will be understoodthat, as used herein, references to the compounds of formula I, II, III,and IV are meant to also include the pharmaceutically acceptable salts,such as the hydrochloride salts.

Compounds of formula I, II, III, and IV are cholecystokinin receptorligands and as such are useful in the treatment, control or preventionof diseases, disorders or conditions responsive to the modulation of oneor more of the cholecystokinin receptors. In particular, the compoundsof formula I, II, III, and IV act as cholecystokinin-1 receptor agonistsuseful in the treatment, control or prevention of diseases, disorders orconditions responsive to the activation of the cholecystokinin-1receptor. Such diseases, disorders or conditions include, but are notlimited to, obesity (by reducing food intake, reducing appetite,increasing metabolic rate, increasing satiety, reducing carbohydratecraving, reducing gastric emptying), diabetes mellitus (by enhancingglucose tolerance, decreasing insulin resistance), bulimia nervosa andrelated eating disorders, dyslipidemia, hypertension, hyperlipidemia,osteoarthritis, cancer, gall stones, cholelithiasis, cholecystitis, gallbladder disease, sleep apnea, depression, anxiety, compulsion, neuroses,irritable bowel syndrome, inflammatory bowel syndrome, constipation,pain, neuroprotective and cognitive and memory enhancement including thetreatment of Alzheimer's disease. Such diseases, conditions anddisorders also include non-obese overweight conditions and normal weightconditions where weight control or management is desired in order toprevent an obese or overweight condition from developing, or to maintaina healthy weight.

The compounds and compositions of the present invention are useful forthe treatment or prevention of disorders associated with excessive foodintake, such as obesity and obesity-related disorders. The obesityherein may be due to any cause, whether genetic or environmental.

The obesity-related disorders herein are associated with, caused by, orresult from obesity. Examples of obesity-related disorders includeovereating, binge eating, bulimia nervosa, hypertension, type 2diabetes, elevated plasma insulin concentrations, hyperinsulinemia,insulin resistance, glucose intolerance, dyslipidemia, hyperlipidemia,endometrial cancer, breast cancer, prostate cancer, kidney cancer, coloncancer, osteoarthritis, obstructive sleep apnea, cholelithiasis,cholecystitis, gallstones, gout, gallbladder disease, abnormal heartrhythms and arrythmias, myocardial infarction, congestive heart failure,coronary heart disease, angina pectoris, sudden death, stroke, metabolicsyndrome, psychological disorders (depression, eating disorders,distorted bodyweight, and low self esteem), and other pathologicalconditions showing reduced metabolic activity or a decrease in restingenergy expenditure as a percentage of total fat-free mass, e.g, childrenwith acute lymphoblastic leukemia. Further examples of obesity-relateddisorders are sexual and reproductive dysfunction, such as polycysticovary disease, infertility, hypogonadism in males and hirsutism infemales, gastrointestinal motility disorders, such as obesity-relatedgastro-esophageal reflux, respiratory disorders, such asobesity-hypoventilation syndrome (Pickwickian syndrome), cardiovasculardisorders, inflammation, such as systemic inflammation of thevasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia,lower back pain, gallbladder disease, gout, and kidney cancer.Additionally, the present compounds are useful in the treatment of anycondition in which it is desirable to lose weight or to reduce foodintake. Additionally, the present compounds are useful in the treatmentof any condition in which it is desirable to enhance cognition andmemory, such as Alzheimer's Disease. The compositions of the presentinvention are also useful for reducing the risk of secondary outcomes ofobesity, such as reducing the risk of left ventricular hypertrophy.Therefore, the present invention provides methods of treatment orprevention of such diseases, conditions and/or disorders modulated byCCK-1 receptor agonists in an animal which comprises administering tothe animal in need of such treatment a compound of formula I, II, III,or IV, in particular a therapeutically or prophylactically effectiveamount thereof.

Some agonists encompassed by formula I, II, III, and IV show highlyselective affinity for the cholecystokinin-1 receptor (CCK-1R) relativeto cholecystokinin-2 receptor CCK-2R (also known as the CCK-B receptor),which makes them especially useful in the prevention and treatment ofobesity, diabetes, and obesity related disorders. Compounds of thepresent invention are at least 500 fold more selective for the CCK-1receptor than for the CCK-2 receptor.

The term “metabolic syndrome”, also known as syndrome X, is defined inthe Third Report of the National Cholesterol Education Program ExpertPanel on Detection, Evaluation and Treatment of High Blood Cholesterolin Adults (ATP-III). E. S. Ford et al., JAMA, vol. 287 (3), Jan. 16,2002, pp 356-359. Briefly, a person is defined as having metabolicsyndrome if the person has three or more of the following symptoms:abdominal obesity, hypertriglyceridemia, low HDL cholesterol, high bloodpressure, and high fasting plasma glucose. The criteria for these aredefined in ATP-III.

The term “diabetes,” as used herein, includes both insulin-dependentdiabetes mellitus (i.e., IDDM, also known as type I diabetes) andnon-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as TypeII diabetes). Type I diabetes, or insulin-dependent diabetes, is theresult of an absolute deficiency of insulin, the hormone which regulatesglucose utilization. Type II diabetes, or insulin-independent diabetes(i.e., non-insulin-dependent diabetes mellitus), often occurs in theface of normal, or even elevated levels of insulin and appears to be theresult of the inability of tissues to respond appropriately to insulin.Most of the Type II diabetics are also obese. The compositions of thepresent invention are useful for treating both Type I and Type IIdiabetes. The compositions are especially effective for treating Type IIdiabetes. The compounds or combinations of the present invention arealso useful for treating and/or preventing gestational diabetesmellitus.

Treatment of diabetes mellitus refers to the administration of acompound or combination of the present invention to treat diabetes. Oneoutcome of treatment may be decreasing the glucose level in a subjectwith elevated glucose levels. Another outcome of treatment may beimproving glycemic control. Another outcome of treatment may bedecreasing insulin levels in a subject with elevated insulin levels.Another outcome of treatment may be decreasing plasma triglycerides in asubject with elevated plasma triglycerides. Another outcome of treatmentmay be lowering LDL cholesterol in a subject with high LDL cholesterollevels. Another outcome of treatment may be increasing HDL cholesterolin a subject with low HDL cholesterol levels. Another outcome may bedecreasing the LDL/HDL ratio in a subject in need thereof. Anotheroutcome of treatment may be increasing insulin sensivity. Anotheroutcome of treatment may be enhancing glucose tolerance in a subjectwith glucose intolerance. Another outcome of treatment may be decreasinginsulin resistance in a subject with increased insulin resistance orelevated levels of insulin. Another outcome may be decreadingtriglycerides in a subject with elevated triglycerides. Yet anotheroutcome may be improving LDL cholestrol, non-HDL cholesterol,triglyceride, HDL cholesterol or other lipid analyte profiles.

Prevention of diabetes mellitus refers to the administration of acompound or combination of the present invention to prevent the onset ofdiabetes in a subject at risk thereof.

“Obesity” is a condition in which there is an excess of body fat. Theoperational definition of obesity is based on the Body Mass Index (BMI),which is calculated as body weight per height in meters squared (kg/m²).“Obesity” refers to a condition whereby an otherwise healthy subject hasa Body Mass Index (BMI) greater than or equal to 30 kg/m², or acondition whereby a subject with at least one co-morbidity has a BMIgreater than or equal to 27 kg/m². An “obese subject” is an otherwisehealthy subject with a Body Mass Index (BMI) greater than or equal to 30kg/m² or a subject with at least one co-morbidity with a BMI greaterthan or equal to 27 kg/m². A “subject at risk of obesity” is anotherwise healthy subject with a BMI of 25 kg/m² to less than 30 kg/m²or a subject with at least one co-morbidity with a BMI of 25 kg/m² toless than 27 kg/m².

The increased risks associated with obesity occur at a lower Body MassIndex (BMI) in Asians. In Asian countries, including Japan, “obesity”refers to a condition whereby a subject with at least oneobesity-induced or obesity-related co-morbidity, that requires weightreduction or that would be improved by weight reduction, has a BMIgreater than or equal to 25 kg/m². in Asian countries, including Japan,an “obese subject” refers to a subject with at least one obesity-inducedor obesity-related co-morbidity that requires weight reduction or thatwould be improved by weight reduction, with a BMI greater than or equalto 25 kg/m². In Asia-Pacific, a “subject at risk of obesity” is asubject with a BMI of greater than 23 kg/m² to less than 25 kg/m².

As used herein, the term “obesity” is meant to encompass all of theabove definitions of obesity.

Obesity-induced or obesity-related co-morbidities include, but are notlimited to, diabetes, non-insulin dependent diabetes mellitus-type II(2), impaired glucose tolerance, impaired fasting glucose, insulinresistance syndrome, dyslipidemia, hypertension, hyperuricacidemia,gout, coronary artery disease, myocardial infarction, angina pectoris,sleep apnea syndrome, Pickwickian syndrome, fatty liver; cerebralinfarction, cerebral thrombosis, transient ischemic attack, orthopedicdisorders, arthritis deformans, lumbodynia, emmeniopathy, andinfertility. In particular, co-morbidities include: hypertension,hyperlipidemia, dyslipidemia, glucose intolerance, cardiovasculardisease, sleep apnea, diabetes mellitus, and other obesity-relatedconditions.

Treatment of obesity and obesity-related disorders refers to theadministration of the compounds or combinations of the present inventionto reduce or maintain the body weight of an obese subject. One outcomeof treatment may be reducing the body weight of an obese subjectrelative to that subject's body weight immediately before theadministration of the compounds or combinations of the presentinvention. Another outcome of treatment may be preventing body weightregain of body weight previously lost as a result of diet, exercise, orpharmacotherapy. Another outcome of treatment may be decreasing theoccurrence of and/or the severity of obesity-related diseases. Thetreatment may suitably result in a reduction in food or calorie intakeby the subject, including a reduction in total food intake, or areduction of intake of specific components of the diet such ascarbohydrates or fats; and/or the inhibition of nutrient absorption;and/or the inhibition of the reduction of metabolic rate; and in weightreduction in subjects in need thereof. The treatment may also result inan alteration of metabolic rate, such as an increase in metabolic rate,rather than or in addition to an inhibition of the reduction ofmetabolic rate; and/or in minimization of the metabolic resistance thatnormally results from weight loss.

Prevention of obesity and obesity-related disorders refers to theadministration of the compounds or combinations of the present inventionto reduce or maintain the body weight of a subject at risk of obesity.One outcome of prevention may be reducing the body weight of a subjectat risk of obesity relative to that subject's body weight immediatelybefore the administration of the compounds or combinations of thepresent invention. Another outcome of prevention may be preventing bodyweight regain of body weight previously lost as a result of diet,exercise, or pharmacotherapy. Another outcome of prevention may bepreventing obesity from occurring if the treatment is administered priorto the onset of obesity in a subject at risk of obesity. Another outcomeof prevention may be decreasing the occurrence and/or severity ofobesity-related disorders if the treatment is administered prior to theonset of obesity in a subject at risk of obesity. Moreover, if treatmentis commenced in already obese subjects, such treatment may prevent theoccurrence, progression or severity of obesity-related disorders, suchas, but not limited to, arteriosclerosis, Type II diabetes, polycysticovary disease, cardiovascular diseases, osteoarthritis, hypertension,dyslipidemia, insulin resistance, hypercholesterolemia,hypertriglyceridemia, and cholelithiasis.

The terms “administration of” and or “administering” a compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to a subject in need of treatment. Theadministration of the compounds of the present invention in order topractice the present methods of therapy is carried out by administeringa therapeutically effective amount of the compound to a subject in needof such treatment or prophylaxis. The need for a prophylacticadministration according to the methods of the present invention isdetermined via the use of well known risk factors.

The term “therapeutically effective amount” as used herein means theamount of the active compound that will elicit the biological or medicalresponse in a tissue, system, subject, mammal, or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician, which includes alleviation of the symptoms of the disorderbeing treated. The novel methods of treatment of this invention are fordisorders known to those skilled in the art. The term “prophylacticallyeffective amount” as used herein means the amount of the active compoundthat will elicit the biological or medical response in a tissue, system,subject, mammal, or human that is being sought by the researcher,veterinarian, medical doctor or other clinician, to prevent the onset ofthe disorder in subjects as risk for obesity or the disorder. Thetherapeutically or prophylactically effective amount, or dosage, of anindividual compound is determined, in the final analysis, by thephysician in charge of the case, but depends on factors such as theexact disease to be treated, the severity of the disease and otherdiseases or conditions from which the patient suffers, the chosen routeof administration, other drugs and treatments which the patient mayconcomitantly require, and other factors in the physician's judgement.

Administration and Dose Ranges

Any suitable route of administration may be employed for providing asubject or mammal, especially a human with an effective dosage of acompound of the present invention. For example, oral, rectal, topical,parenteral, ocular, pulmonary, nasal, and the like may be employed.Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, creams, ointments, aerosols, and the like.Preferably the compound of Formula I, II, III, or IV is administeredorally or topically.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

When treating obesity, in conjunction with diabetes and/orhyperglycemia, or alone, generally satisfactory results are obtainedwhen the compound of formula I, II, III, or IV is administered at adaily dosage of from about 0.001 milligram to about 50 milligrams perkilogram of animal body weight, preferably given in a single dose or individed doses two to six times a day, or in sustained release form. Inthe case of a 70 kg adult human, the total daily dose will generally befrom about 0.07 milligrams to about 3500 milligrams. This dosage regimenmay be adjusted to provide the optimal therapeutic response.

When treating diabetes mellitus and/or hyperglycemia, as well as otherdiseases or disorders for which the compound of formula I, II, III, orIV is useful, generally satisfactory results are obtained when thecompounds of the present invention are administered at a daily dosage offrom about 0.001 milligram to about 50 milligram per kilogram of animalbody weight, preferably given in a single dose or in divided doses twoto six times a day, or in sustained release form. In the case of a 70 kgadult human, the total daily dose will generally be from about 0.07milligrams to about 3500 milligrams. This dosage regimen may be adjustedto provide the optimal therapeutic response.

When treating dyslipidemia, bulimia nervosa, and gallstones satisfactoryresults are obtained when the compound of formula I, II, III, or IV isadministered at a daily dosage of from about 0.001 milligram to about 50milligrams per kilogram of animal body weight, preferably given in asingle dose or in divided doses two to six times a day, or in sustainedrelease form. In the case of a 70 kg adult human, the total daily dosewill generally be from about 0.07 milligrams to about 3500 milligrams.This dosage regimen may be adjusted to provide the optimal therapeuticresponse.

In the case where an oral composition is employed, a suitable dosagerange is, e.g. from about 0.01 mg to about 1500 mg of a compound ofFormula I, II, III, or IV per day, preferably from about 0.1 mg to about600 mg per day, more preferably from about 0.1 mg to about 100 mg perday. For oral administration, the compositions are preferably providedin the form of tablets containing from 0.01 to 1,000 mg, preferably0.01, 0.05, 0.1, 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 100, 250,500, 600, 750, 1000, 1250 or 1500 milligrams of the active ingredientfor the symptomatic adjustment of the dosage to the patient to betreated.

For use where a composition for intranasal administration is employed,intranasal formulations for intranasal administration comprising0.001-10% by weight solutions or suspensions of the compound of formulaI, II, III, or IV in an acceptable intranasal formulation may be used.

For use where a composition for intravenous administration is employed,a suitable dosage range is from about 0.001 mg to about 50 mg,preferably from 0.01 mg to about 50 mg, more preferably 0.1 mg to 10 mg,of a compound of formula I, II, III, or IV per kg of body weight perday. This dosage regimen may be adjusted to provide the optimaltherapeutic response. It may be necessary to use dosages outside theselimits in some cases.

For the treatment of diseases of the eye, ophthalmic preparations forocular administration comprising 0.001-1% by weight solutions orsuspensions of the compound of formula I, II, III, or IV in anacceptable ophthalmic formulation may be used.

The magnitude of prophylactic or therapeutic dosage of the compounds ofthe present invention will, of course, vary depending on the particularcompound employed, the mode of administration, the condition beingtreated and the severity of the condition being treated. It will alsovary according to the age, weight and response of the individualpatient. Such dosage may be ascertained readily by a person skilled inthe art.

A compound of formula I, II, III, or IV may be used in combination withother drugs that are used in the treatment/prevention/suppression oramelioration of the diseases or conditions for which compounds offormula I, II, III, and IV are useful. Such other drugs may beadministered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of formula I, II, III,or IV. When a compound of formula I, II, III, or IV is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofFormula I is preferred. Accordingly, the pharmaceutical compositions ofthe present invention include those that also contain one or more otheractive ingredients, in addition to a compound of formula I, II, III, orIV. Examples of other active ingredients that may be combined with acompound of formula I, II, III, and IV for the treatment or preventionof obesity and/or diabetes, either administered separately or in thesame pharmaceutical compositions, include, but are not limited to:

(a) insulin sensitizers including (i) PPARγ antagonists such asglitazones (e.g. ciglitazone; darglitazone; englitazone; isaglitazone(MCC-555); pioglitazone; rosiglitazone; troglitazone; tularik;BRIL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641, and LY-300512, and thelike), and compounds disclosed in WO 97/10813, WO 97/27857, WO 97/28115,WO 97/28137, and WO 97/27847; (iii) biguanides such as metformin andphenformin;

(b) insulin or insulin mimetics, such as biota, LP-100, novarapid,insulin detemir, insulin lispro, insulin glargine, insulin zincsuspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7)(insulintropin); and GLP-1 (7-36)-NH₂);

(c) sulfonylureas, such as acetohexamide; chlorpropamide; diabinese;glibenclamide; glipizide; glyburide; glimepiride; gliclazide;glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide;

(d) α-glucosidase inhibitors, such as acarbose, adiposine; camiglibose;emiglitate; miglitol; voglibose; pradimicin-Q; salbostatin; trestatin,tendamistate, CKD-711; MDL-25,637; MDL-73,945; and MOR 14, and the like;

(e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin,rivastatin, rosuvastatin, simvastatin, and other statins), (ii) bileacid absorbers/sequestrants, such as cholestyramine, colestipol,dialkylaminoalkyl derivatives of a cross-linked dextran; Colestid®;LoCholest®, and the like, (ii) nicotinyl alcohol, nicotinic acid or asalt thereof, (iii) proliferator-activater receptor α agonists such asfenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate andbenzafibrate), (iv) inhibitors of cholesterol absorption such as stanolesters, beta-sitosterol, sterol glycosides such as tiqueside; andazetidinones such as ezetimibe, and the like, and (acyl CoA:cholesterolacyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide,(v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii)thyromimetics;

(1) PPARα agonists such as beclofibrate, benzafibrate, ciprofibrate,clofibrate, etofibrate, fenofibrate, and gemfibrozil; and other fibricacid derivatives, such as Atromid®, Lopid® and Tricor®, and the like,and PPARα agonists as described in WO 97/36579 by Glaxo;

(g) PPARδ agonists, such as those disclosed in WO97/28149;

(h) PPARα/δ agonists, such as muraglitazar, and the compounds disclosedin U.S. Pat. No. 6,414,002;

(i) smoking cessation agents, such as a nicotine agonist or a partialnicotine agonist such as varenicline, or a monoamine oxidase inhibitor(MAOI), or another active ingredient demonstrating efficacy in aidingcessation of tobacco consumption; for example, an antidepressant such asbupropion, doxepine, ornortriptyline; or an anxiolytic such as buspironeor clonidine; and

j) anti-obesity agents, such as (1) growth hormone secretagogues, growthhormone secretagogue receptor agonists/antagonists, such as NN703,hexarelin, ME-0677, SM-130686, CP-424,391, L-692,429, and L-163,255, andsuch as those disclosed in U.S. Pat. Nos. 5,536,716, and 6,358,951, U.S.Patent Application Nos. 2002/049196 and 2002/022637, and PCT ApplicationNos. WO 01/56592 and WO 02/32888; (2) protein tyrosine phosphatase-1B(PTP-1B) inhibitors; (3) cannabinoid receptor ligands, such ascannabinoid CB₁ receptor antagonists or inverse agonists, such asrimonabant (Sanofi Synthelabo), AMT-251, and SR-14778 and SR 141716A(Sanofi Synthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer), and thosedisclosed in U.S. Pat. Nos. 5,532,237, 4,973,587, 5,013,837, 5,081,122,5,112,820, 5,292,736, 5,624,941, 6,028,084, PCT Application Nos. WO96/33159, WO 98/33765, WO98/43636, WO98/43635, WO 01/09120, WO98/31227,WO98/41519, WO98/37061, WO00/10967, WO00/10968, WO97/29079, WO99/02499,WO 01/58869, WO 01/64632, WO 01/64633, WO 01/64634, WO02/076949, WO03/007887, WO 04/048317, and WO 05/000809; and EPO Application No.EP-658546, EP-656354, EP-576357; (4) anti-obesity serotonergic agents,such as fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5)β3-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda),CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A,CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A, and such asthose disclosed in U.S. Patent Application Nos. 5,705,515, and U.S. Pat.No. 5,451,677 and PCT Patent Publications WO94/18161, WO95/29159,WO97/46556, WO98/04526 and WO98/32753, WO 01/74782, and WO 02/32897; (6)pancreatic lipase inhibitors, such as orlistat (Xenical®), TritonWR1339, RHC80267, lipstatin, tetrahydrolipstatin, teasaponin,diethylumbelliferyl phosphate, and those disclosed in PCT ApplicationNo. WO 01/77094; (7) neuropeptide Y1 antagonists, such as BIBP3226,J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A, and thosedisclosed in U.S. Pat. No. 6,001,836, and PCT Patent Publication Nos. WO96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO01/85173, and WO 01/89528; (8) neuropeptide Y5 antagonists, such asGW-569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR240662,FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170,SR-120562A, SR-120819A and JCF-104, and those disclosed in U.S. Pat.Nos. 6,057,335; 6,043,246; 6,140,354; 6,166,038; 6,180,653; 6,191,160;6,313,298; 6,335,345; 6,337,332; 6,326,375; 6,329,395; 6,340,683;6,388,077; 6,462,053; 6,649,624; and 6,723,847, hereby incorporated byreference in their entirety; European Patent Nos. EP-01010691, andEP-01044970; and PCT International Patent Publication Nos. WO 97/19682,WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/24768; WO98/25907; WO 98/25908; WO 98/27063, WO 98/47505; WO 98/40356; WO99/15516; WO 99/27965; WO 00/64880, WO 00/68197, WO 00/69849, WO01/09120, WO 01/14376; WO 01/85714, WO 01/85730, WO 01/07409, WO01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO02/49648; WO 02/094825; WO 03/014083; WO 03/10191; WO 03/092889; WO04/002986; and WO 04/031175; (9) melanin-concentrating hormone (MCH)receptor antagonists, such as those disclosed in WO 01/21577 and WO01/21169; (10) melanin-concentrating hormone 1 receptor (MCH1R)antagonists, such as T-226296 (Takeda), and those disclosed in PCTPatent Application Nos. WO 01/82925, WO 01/87834, WO 02/051809, WO02/06245, WO 02/076929, WO 02/076947, WO 02/04433, WO 02/51809, WO02/083134, WO 02/094799, WO 03/004027, and Japanese Patent ApplicationNos. JP 13226269, and JP 2004-139909; (11) melanin-concentrating hormone2 receptor (MCH2R) agonist/antagonists; (12) orexin-1 receptorantagonists, such as SB-334867-A, and those disclosed in PCT PatentApplication Nos. WO 01/96302, WO 01/68609, WO 02/51232, and WO 02/51838;(13) serotonin reuptake inhibitors such as fluoxetine, paroxetine, andsertraline, and those disclosed in U.S. Pat. No. 6,365,633, and PCTPatent Application Nos. WO 01/27060 and WO 01/162341; (14) melanocortinagonists, such as Melanotan II, CHIR86036 (Chiron), ME-10142, andME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14 (Palatin);(15) other MC4R (melanocortin 4 receptor) agonists, such as thosedisclosed in: U.S. Pat. Nos. 6,410,548; 6,294,534; 6,350,760; 6,458,790;6,472,398; 6,376,509; and 6,818,658; US Patent Publication No.US2002/0137664; US2003/0236262; US2004/009751; US2004/0092501; and PCTApplication Nos. WO 99/64002; WO 00/74679; WO 01/70708; WO 01/70337; WO01/74844; WO 01/91752; WO 01/991752; WO 02/15909; WO 02/059095; WO02/059107; WO 02/059108; WO 02/059117; WO 02/067869; WO 02/068387; WO02/068388; WO 02/067869; WO 02/11715; WO 02/12166; WO 02/12178; WO03/007949; WO 03/009847; WO 04/024720; WO 04/078716; WO 04/078717; WO04/087159; WO 04/089307; and WO 05/009950; (16) 5HT-2 agonists; (17)5HT2C (serotonin receptor 2C) agonists, such as BVT933, DPCA37215,WAY161503, R1065, and those disclosed in U.S. Pat. No. 3,914,250, andPCT Application Nos. WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548,WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457; (18) galaninantagonists; (19) CCK agonists; (20) other CCK-1 (cholecystokinin-A)agonists, such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 andSR146131, and those discribed in U.S. Pat. No. 5,739,106; (21) GLP-1agonists; (22) corticotropin-releasing hormone agonists; (23) histaminereceptor-3 (H3) modulators; (24) histamine receptor-3 (H3)antagonists/inverse agonists, such as hioperamide,3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit,iodophenpropit, imoproxifan, GT2394 (Gliatech), and those described anddisclosed in PCT Application No. WO 02/15905, andO—[3-(1H-imidazol-4-yl)propanol]-carbamates (Kiec-Kononowicz, K. et al.,Pharmazie, 55:349-55 (2000)), piperidine-containing histamineH3-receptor antagonists (Lazewska, D. et al., Pharmazie, 56:927-32(2001), benzophenone derivatives and related compounds (Sasse, A. etal., Arch. Pharm. (Weinheim) 334:45-52 (2001)), substitutedN-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55:83-6 (2000)),and proxifan derivatives (Sasse, A. et al., J. Med. Chem. 43:3335-43(2000)); (25) β-hydroxy steroid dehydrogenase-1 inhibitors (β-HSD-1);26) PDE (phosphodiesterase) inhibitors, such as theophylline,pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide,rolipram, and cilomilast; (27) phosphodiesterase-3B (PDE3B) inhibitors;(28) NE (norepinephrine) transport inhibitors, such as GW 320659,despiramine, talsupram, and nomifensine; (29) ghrelin receptorantagonists, such as those disclosed in PCT Application Nos. WO01/87335, and WO 02/08250; (30) leptin, including recombinant humanleptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin(Amgen); (31) leptin derivatives, such as those disclosed in U.S. Pat.Nos. 5,552,524, 5,552,523, 5,552,522, 5,521,283, and PCT InternationalPublication Nos. WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO96/23517, WO 96/23518, WO 96/23519, and WO 96/23520; (32) BRS3 (bombesinreceptor subtype 3) agonists such as[D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and[D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed inPept. Sci. 2002 August; 8(8): 461-75); (33) CNTF (Ciliary neurotrophicfactors), such as GI-181771 (Glaxo-SmithKline), SR146131 (SanofiSynthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTFderivatives, such as axokine (Regeneron), and those disclosed in PCTApplication Nos. WO 94/09134, WO 98/22128, and WO 99/43813; (35)monoamine reuptake inhibitors, such as sibutramine, and those disclosedin U.S. Pat. Nos. 4,746,680, 4,806,570, and 5,436,272, U.S. PatentPublication No. 2002/0006964 and PCT Application Nos. WO 01/27068, andWO 01/62341; (36) UCP-1 (uncoupling protein-1), 2, or 3 activators, suchas phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), retinoic acid, and those disclosed in PCT PatentApplication No. WO 99/00123; (37) thyroid hormone β agonists, such asKB-2611 (KaroBioBMS), and those disclosed in PCT Application No. WO02/15845, and Japanese Patent Application No. JP 2000256190; (38) FAS(fatty acid synthase) inhibitors, such as Cerulenin and C75; (39) DGAT1(diacylglycerol acyltransferase 1) inhibitors; (40) DGAT2(diacylglycerol acyltransferase 2) inhibitors; (41) ACC2 (acetyl-CoAcarboxylase-2) inhibitors; (42) glucocorticoid antagonists; (43)acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M.et al., Obesity Research, 9:202-9 (2001); (44) dipeptidyl peptidase IV(DP-IV) inhibitors, such as isoleucine thiazolidide, valine pyrrolidide,NVP-DPP728, LAF237, P93/01, TSL 225, TMC-2A/2B/2C, FE 999011,P9310/K364, VIP 0177, SDZ 274-444 and sitagliptin; and the compoundsdisclosed in U.S. Patent No. 6,699,871, which is incorporated herein byreference; and International Patent Application Nos. WO 03/004498; WO03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/000250; WO03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; andWO 03/000181; (46) dicarboxylate transporter inhibitors; (47) glucosetransporter inhibitors; (48) phosphate transporter inhibitors; (49)Metformin (Glucophage®); and (50) Topiramate (Topimax®); and (50)peptide YY, PYY 3-36, peptide YY analogs, derivatives, and fragmentssuch as BIM-43073D, BIM-43004C (Olitvak, D. A. et al., Dig. Dis. Sci.44(3):643-48 (1999)), and those disclosed in U.S. Pat. No. 5,026,685,U.S. Pat. No. 5,604,203, U.S. Pat. No. 5,574,010, U.S. Pat. No.5,696,093, U.S. Pat. No. 5,936,092, U.S. Pat. No. 6,046,162, U.S. Pat.No. 6,046,167, U.S. Pat. No. 6,093,692, U.S. Pat. No. 6,225,445, U.S.Pat. No. 5,604,203, U.S. Pat. No. 4,002,531, U.S. Pat. No. 4,179,337,U.S. Pat. No. 5,122,614, U.S. Pat. No. 5,349,052, U.S. Pat. No.5,552,520, U.S. Pat. No. 6,127,355, WO 95/06058, WO 98/32466, WO03/026591, WO 03/057235, WO 03/027637, and WO 2004/066966, which areincorporated herein by reference; (51) Neuropeptide Y2 (NPY2) receptoragonists such NPY3-36, N acetyl [Leu(28,31)] NPY 24-36, TASP-V, andcyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4 (NPY4)agonists such as pancreatic peptide (PP) as described in Batterham etal., J. Clin. Endocrinol. Metab. 88:3989-3992 (2003), and other Y4agonists such as 1229U91; (54) cyclo-oxygenase-2 inhibitors such asetoricoxib, celecoxib, valdecoxib, parecoxib, lumiracoxib, BMS347070,tiracoxib or JTE522, ABT963, CS502 and GW406381, and pharmaceuticallyacceptable salts thereof; (55) Neuropeptide Y1 (NPY1) antagonists suchas BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A andthose disclosed in U.S. Pat. No. 6,001,836; and PCT Application Nos. WO96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO01/85173, and WO 01/89528; (56) Opioid antagonists such as nalmefene(Revex®), 3-methoxynaltrexone, naloxone, naltrexone, and those disclosedin: PCT Application No. WO 00/21509; (57) 11β, HSD-1 (11-beta hydroxysteroid dehydrogenase type 1) inhibitors such as BVT 3498, BVT 2733, andthose disclosed in WO 01/90091, WO 01/90090, WO 01/90092, and US PatentNo. U.S. Pat. No. 6,730,690 and US Publication No. US 2004-0133011,which are incorporated by reference herein in their entirety; and (58)aminorex; (59) amphechloral; (60) amphetamine; (61) benzphetamine; (62)chlorphentermine; (63) clobenzorex; (64) cloforex; (65) clominorex; (66)clortermine; (67) cyclexedrine; (68) dextroamphetamine; (69)diphemethoxidine, (70) N-ethylamphetamine; (71) fenbutrazate; (72)fenisorex; (73) fenproporex; (74) fludorex; (75) fluminorex; (76)furfurylmethylamphetamine; (77) levamfetamine; (78) levophacetoperane;(79) mefenorex; (80) metamfepramone; (81) methamphetamine; (82)norpseudoephedrine; (83) pentorex; (84) phendimetrazine; (85)phenmetrazine; (86) picilorex; (87) phytopharm 57; (88) zonisamide, (89)neuromedin U and analogs or derivatives thereof, (90) oxyntomodulin andanalogs or derivatives thereof; (91) Neurokinin-1 receptor antagonists(NK-1 antagonists) such as the compounds disclosed in: U.S. Pat. Nos.5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270,5,494,926, 5,496,833, and 5,637,699; PCT International PatentPublication Nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688,92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677,92/22569, 93/00330, 93/00331, 93/01159, 93/01165,93/01169,93/01170,93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023,93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402,94/02461, 94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625,94/07843, 94/08997,94/10165, 94/10167, 94/10168, 94/10170, 94/11368,94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500,94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645,95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679,95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525,95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181,96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643,96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214,96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671,97/17362, 97/18206, 97/19084, 97/19942, 97/21702, and 97/49710; and (92)Qnexa.

Specific compounds of use in combination with a compound of the presentinvention include: simvastatin, mevastatin, ezetimibe, atorvastatin,sitagliptin, metformin, sibutramine, orlistat, Qnexa, topiramate,naltrexone, bupriopion, phentermine, and losartan, losartan withhydrochlorothiazide. Specific CB1 antagonists/inverse agonists of use incombination with a compound of the present invention include: thosedescribed in WO03/077847, including:N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide,N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,and pharmaceutically acceptable salts thereof; as well as those inWO05/000809, which includes the following:3-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-3-(3,5-difluorophenyl)-2,2-dimethylpropanenitrile,1-{1-[1-(4-chlorophenyl)pentyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol.3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile,3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile,3-((4-chlorophenyl){3-[1-(3,5-difluorophenyl)-2,2-dimethylpropyl]azetidin-1-yl}methyl)benzonitrile,3-((1S)-1-{1-[(S)-(3-cyanophenyl)(4-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(4H-1,2,4-triazol-4-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,and 5-((4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)thiophene-3-carbonitrile,and pharmaceutically acceptable salts thereof; as well as:3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(4-chlorophenyl)(3-(1S)-2-fluoro-1-[3-fluoro-5-(1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(3-{(1S)-1-[3-(5-amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-fluoro-2-methylpropyl}azetidin-1-yl)(4-chlorophenyl)methyl]benzonitrile,3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(3-{(1S)-1-[3-(5-amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-fluoro-2-methylpropyl}azetidin-1-yl)(4-cyanophenyl)methyl]benzonitrile,3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(4-chlorophenyl)(3-{(S)-2-fluoro-1-[3-fluoro-5-(1,2,4-oxadiazol-3-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]-methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1H-tetrazole,5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1-methyl-1H-tetrazole,5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-2-methyl-2H-tetrazole,3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,5-{3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl]phenyl}-1,3,4-oxadiazol-2(3H)-one,3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-((S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadiazol-2-yl)phenyl](4-chlorophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,3-((1S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadiazol-2-yl)phenyl](4-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,5-[3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one,5-[3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one,4-{(S)-{3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}-benzonitrile,and pharmaceutically acceptable salts thereof.

Specific NPY5 antagonists of use in combination with a compound of thepresent invention include:3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaiso-benzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, and pharmaceutically acceptable saltsand esters thereof.

Specific ACC-1/2 inhibitors of use in combination with a compound of thepresent invention include:1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;(5-{1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}-2H-tetrazol-2-yl)methylpivalate;5-{1′-[(8-cyclopropyl-4-methoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinicacid;1′-(8-methoxy-4-morpholin-4-yl-2-naphthoyl)-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;and1′-[(4-ethoxy-8-ethylquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;and pharmaceutically acceptable salts and esters thereof. Specific MCH1Rantagonist compounds of use in combination with a compound of thepresent invention include:1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one,4-[(4-fluorobenzyl)oxy]-1-{4-[(1-isopropylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,1-[4-(azetidin-3-yloxy)phenyl]-4-[(5-chloropyridin-2-yl)methoxy]pyridin-2(1H)-one,4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-propylazetidin-3-yl)oxy]phenyl)pyridin-2(1H)-one,and4-[(5-chloropyridin-2-yl)methoxy]-1-(4-{[(2S)-1-ethylazetidin-2-yl]methoxy}phenyl)pyridin-2(1H)-one,or a pharmaceutically acceptable salt thereof.

Specific DP-IV inhibitors of use in combination with a compound of thepresent invention are selected from7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine.In particular, the compound of formula I is favorably combined with7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine,and pharmaceutically acceptable salts thereof.

Specific H3 (histamine H3) antagonists/inverse agonists of use incombination with a compound of the present invention include: thosedescribed in WO05/077905, including:3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[2,3-d]-pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,2-ethyl-3-(4-(3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone,3-{4[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[4,3-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,2,5-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone,5-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,5-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,7-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,5-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,2-methyl-3-(4-(3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,6-methoxy-2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,and pharmaceutically acceptable salts thereof.

Specific CCK1R agonists of use in combination with a compound of thepresent invention include:3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid;3-(4-([1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid;3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid;3-(4-{[1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; and3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; and pharmaceutically acceptable salts thereof. Specific MC4Ragonists of use in combination with a compound of the present inventioninclude: 1)(5S)-1′-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];2)(SR)-1′-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)-piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];3)2-(1′-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-yl)-2-methylpropanenitrile;4)1′-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];5)N-[(3R,4R)-3-({3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-1′H,5H-spiro[furo-[3,4-b]pyridine-7,4′-piperidin]-1′-yl)}carbonyl)-4-(2,4-difluorophenyl)-cyclopentyl]-N-methyltetrahydro-2H-pyran-4-amine;6)2-[3-chloro-1′-({(1R,2R)-2-(2,4-difluorophenyl)-4-[methyl(tetrahydro-2H-pyran-4-yl)amino]-cyclopentyl}-carbonyl)-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-yl]-2-methyl-propane-nitrile;and pharmaceutically acceptable salts thereof. Still further,neurokinin-1 (NK-1) receptor antagonists may be favorably employed incombination with a compound of the present invention. NK-1 receptorantagonists of use in the present invention are fully described in theart. Specific neurokinin-1 receptor antagonists of use in the presentinvention include:(±)-(2R3R,2S3S)-N-{[2-cyclopropoxy-5-(trifluoromethoxy)-phenyl]methyl}-2-phenylpiperidin-3-amine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;aperpitant; CJ17493; GW597599; GW679769; R673; R067319; R1124; R1204;SSR146977; SSR240600; T-2328; and T2763.; or a pharmaceuticallyacceptable salts thereof.

Examples of other anti-obesity agents that can be employed incombination with a compound of formula I, II, III, or IV are disclosedin “Patent focus on new anti-obesity agents,” Exp. Opin. Ther. Patents,10: 819-831 (2000); “Novel anti-obesity drugs,” Exp. Opin. Invest.Drugs, 9: 1317-1326 (2000); and “Recent advances in feeding suppressingagents: potential therapeutic strategy for the treatment of obesity,Exp. Opin. Ther. Patents, 11: 1677-1692 (2001). The role of neuropeptideY in obesity is discussed in Exp. Opin. Invest. Drugs, 9: 1327-1346(2000). Cannabinoid receptor ligands are discussed in Exp. Opin. Invest.Drugs, 9: 1553-1571 (2000).

The instant invention also includes administration of a singlepharmaceutical dosage formulation which contains both the CCK-1R ligandor agonist in combination with a second active ingredient, as well asadministration of each active agent in its own separate pharmaceuticaldosage formulation. Where separate dosage formulations are used, theindividual components of the composition can be administered atessentially the same time, i.e., concurrently, or at separatelystaggered times, i.e. sequentially prior to or subsequent to theadministration of the other component of the composition. The instantinvention is therefore to be understood to include all such regimes ofsimultaneous or alternating treatment, and the terms “administration”and “administering” are to be interpreted accordingly. Administration inthese various ways are suitable for the present compositions as long asthe beneficial pharmaceutical effect of the combination of the CCK-1Rligand or agonist and the second active ingredient is realized by thepatient at substantially the same time. Such beneficial effect ispreferably achieved when the target blood level concentrations of eachactive ingredient are maintained at substantially the same time. It ispreferred that the combination of the CCK-1R ligand or agonist and thesecond active ingredient be co-administered concurrently on a once-a-daydosing schedule; however, varying dosing schedules, such as the CCK-1Rligand or agonist once a day and the second active ingredient once,twice or more times per day or the CCK-1R ligand or agonist three timesa day and the second active ingredient once, twice or more times perday, is also encompassed herein. A single oral dosage formulationcomprised of both a CCK-1R ligand or agonist and a second activeingredient is preferred. A single dosage formulation will provideconvenience for the patient, which is an important considerationespecially for patients with diabetes or obese patients who may be inneed of multiple medications.

The compounds in the combinations of the present invention may beadministered separately, therefore the invention also relates tocombining separate pharmaceutical compositions into a kit form. The kit,according to this invention, comprises two separate pharmaceuticalcompositions: a first unit dosage form comprising a prophylactically ortherapeutically effective amount of the cholecystokinin-1 receptoragonist, or a pharmaceutically acceptable salt or ester thereof, and apharmaceutically acceptable carrier or diluent in a first unit dosageform, and a second unit dosage form comprising a prophylactically ortherapeutically effective amount of the second active ingredient ordrug, or a pharmaceutically acceptable salt or ester thereof, and apharmaceutically acceptable carrier or diluent in a second unit dosageform. In one embodiment, the kit further comprises a container. Suchkits are especially suited for the delivery of solid oral forms such astablets or capsules. Such a kit preferably includes a number of unitdosages. Such kits can include a card having the dosages oriented in theorder of their intended use. An example of such a kit is a “blisterpack”. Blister packs are well known in the packaging industry and arewidely used for packaging pharmaceutical unit dosage forms. If desired,a memory aid can be provided, for example in the form of numbers,letters, or other markings or with a calendar insert, designating thedays or time in the treatment schedule in which the dosages can beadministered.

Another aspect of the present invention provides pharmaceuticalcompositions which comprise a compound of formula I, II, III, or IV, asan active ingredient or a pharmaceutically acceptable salt thereof, andmay also contain a pharmaceutically acceptable carrier and optionallyother therapeutic ingredients. The term “pharmaceutically acceptablesalts” refers to salts prepared from pharmaceutically acceptablenon-toxic bases or acids including inorganic bases or acids and organicbases or acids.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In practical use, the compounds of formula I, II, III, and IV can becombined as the active ingredient in intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier may take a wide variety of formsdepending on the form of preparation desired for administration, e.g.,oral or parenteral (including intravenous). In preparing thecompositions for oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like in thecase of oral liquid preparations, such as, for example, suspensions,elixirs and solutions; or carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents and the like in the case of oral solidpreparations such as, for example, powders, hard and soft capsules andtablets, with the solid oral preparations being preferred over theliquid preparations.

Because of their ease of administration, tablets and capsules representthe typical oral dosage unit form, in which case solid pharmaceuticalcarriers are typically employed. If desired, tablets may be coated bystandard aqueous or nonaqueous techniques. Such compositions andpreparations should contain at least 0.1 percent of active compound. Thepercentage of active compound in these compositions may, of course, bevaried and may conveniently be between about 2 percent to about 60percent of the weight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that an effective dosagewill be obtained. The active compounds can also be administeredintranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil. Various othermaterials may be present as coatings or to modify the physical form ofthe dosage unit. For instance, tablets may be coated with shellac, sugaror both. A syrup or elixir may contain, in addition to the activeingredient, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and a flavoring such as cherry or orange flavor.

Compounds of formula I, II, III, or IV may also be administeredparenterally. Solutions or suspensions of these active compounds can beprepared in water suitably mixed with a surfactant such ashydroxy-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

The compounds of formula I, II, III, and IV of the present invention canbe prepared according to the procedures of the following Schemes andExamples, using appropriate materials and are further exemplified by thefollowing specific examples. Moreover, by utilizing the proceduresdescribed herein, one of ordinary skill in the art can readily prepareadditional compounds of the present invention claimed herein. Thecompounds illustrated in the examples are not, however, to be construedas forming the only genus that is considered as the invention. TheExamples further illustrate details for the preparation of the compoundsof the present invention. Those skilled in the art will readilyunderstand that known variations of the conditions and processes of thefollowing preparative procedures can be used to prepare these compounds.The instant compounds are generally isolated in the form of theirpharmaceutically acceptable salts, such as those described previouslyhereinabove. The free amine bases corresponding to the isolated saltscan be generated by neutralization with a suitable base, such as aqueoussodium hydrogencarbonate, sodium carbonate, sodium hydroxide, andpotassium hydroxide, and extraction of the liberated amine free baseinto an organic solvent followed by evaporation. The amine free baseisolated in this manner can be further converted into anotherpharmaceutically acceptable salt by dissolution in an organic solventfollowed by addition of the appropriate acid and subsequent evaporation,precipitation, or crystallization. All temperatures are degrees Celsiusunless otherwise noted. Mass spectra (MS) were measured byelectron-spray ion-mass spectroscopy.

The phrase “standard peptide coupling reaction conditions” meanscoupling a carboxylic acid with an amine using an acid activating agentsuch as EDC, DCC, and BOP in an inert solvent such as dichloromethane inthe presence of a catalyst such as HOBT. The use of protecting groupsfor the amine and carboxylic acid functionalities to facilitate thedesired reaction and minimize undesired reactions is well documented.Conditions required to remove protecting groups are found in standardtextbooks such as Greene, T, and Wuts, P. G. M., Protective Groups inOrganic Synthesis, John Wiley & Sons, Inc., New York, N.Y., 1991. CBZand BOC are commonly used protecting groups in organic synthesis, andtheir removal conditions are known to those skilled in the art. Forexample, CBZ may be removed by catalytic hydrogenation in the presenceof a noble metal or its oxide such as palladium on activated carbon in aprotic solvent such as methanol or ethanol. In cases where catalytichydrogenation is contraindicated due to the presence of otherpotentially reactive functionalities, removal of CBZ groups can also beachieved by treatment with a solution of hydrogen bromide in acetic acidor by treatment with a mixture of TFA and dimethylsulfide. Removal ofBOC protecting groups is carried out with a strong acid, such astrifluoroacetic acid, hydrochloric acid, or hydrogen chloride gas, in asolvent such as methylene chloride, methanol, or ethyl acetate.

Abbreviations Used in the Description of the Preparation of theCompounds of the Present Invention: BOC (Boc) is t-butyloxycarbonyl, BOPis benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate, Bn is benzyl, Bu is butyl, calc. or calc'd isCalculated, celite is Celite™ diatomaceous earth, CBZ (Cbz) isbenzyloxycarbonyl, c-hex is cyclohexyl, c-pen is cyclopentyl, c-pro iscyclopropyl, DCC is dicyclohexylcarbodiimide, DEAD is diethylazodicarboxylate, DIEA is diisopropyl-ethylamine, DMAP is4-dimethylaminopyridine, DMF is N,N-dimethylformamide, dppf is1,1′-bis(diphenylphosphino)ferrocene, EDC is1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, eq is equivalent(s),ES-MS and ESI-MS are electron spray ion-mass spectroscopy, Et is ethyl,EtOAc is ethyl acetate, g is gram(s), h or hr is hour(s), HATU isO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, HMPA is hexamethyl phosphoramide, HOAc is aceticacid, HOAT is 1-hydroxy-7-azabenzotriazole, HOBt or HOBT is1-hydroxybenzotriazole, HPLC is high performance liquid chromatography;h, hr and hrs is hours; i-Pr is —CH(CH₃)₂, LC/MS or LC-MASS is liquidchromatography mass spectrum, LDA is lithium diisopropylamide, CCK-xR ischolecystokinin receptor (x being a number), L is liter, M is molar, Meis methyl, MeOH is methanol, min is minutes, ME is molecular formula,min is minutes, mg is milligram(s), mL is milliliter, mmol ismillimole(s), MPLC is medium pressure liquid chromatography, MS is massspectrum, Ms is methane sulfonyl, MTBE is tert-butyl methyl ether, N isnormal, n-Bu is —(CH₂)₃CH₃, n-Hex is —(CH₂)₅CH₃, n-Pent is —(CH₂)₄—CH₃,n-Pr is —(CH₂)₂CH₃, NaHMDS is sodium hexamethyl disilazide, NaOtBu issodium tert-butoxide, NMM is N-Methylmorpholine, NMO isN-Methylmorpholine-N-oxide, OTf is trifluoromethanesulfonyl, Pd₂(dba)₃is tris(dibenzylideneacetone) dipalladium (0), Ph is phenyl, Phe isphenyl alanine, Pr is propyl, i-Pr is isopropyl, prep. is prepared,PyBOP is benzotriazol-1-yloxytripyrrolidine-phosphoniumhexafluorophosphate, PyBrop is bromo-tris-pyrrolidino-phosphoniumhexafluoro-phosphate, r.t. or rt is room temperature, SCF CO₂ S is supercritical fluid carbon dioxide, t-Bu is —C(CH₃)₃, TEA or Et₃N istriethylamine, Tf is triflate or trifluoromethanesulfonate, TFA istrifluoroacetic acid, THF is tetrahydrofuran, and TLC is thin-layerchromatography.

Reaction Schemes 1-10 illustrate the methods employed in the synthesisof the compounds of the present invention of formula I, II, III, and IV.All substituents are as defined above unless indicated otherwise.

The synthesis of the novel compounds of formula I, II, III, and IV,which are the subject of this invention may be accomplished by one ormore of several similar routes. The compounds of the present inventioncan be prepared from one such route using diaryl imidazole carboxamidessuch as those of formula VI and a substituted piperazine such as VII, ora piperidine such as VIII via standard coupling conditions followed byadditional modifications. The preparation of these intermediates isdescribed in the following Schemes, wherein X, Y, and R¹ to R¹⁶ aredefined above.

Intermediates of formula VI are known in the literature or may beprepared by a variety of methods familiar to those skilled in the art.One route described in the literature (J. H. M. Lange, et. al. J. Med.Chem. 2005, 48, 1823 and I. K. Khanna, et. al. 3. Med. Chem. 1997, 40,1634) is illustrated in Scheme 1. Intermediates of formula 1 and 2,which are either commercially available or known in the literature, aretreated with a base such as potassium or sodium bis(trimethylsilyl)amideto provide the diaryl amidine 3. Heating amidine 3 with methyl or ethylbromopyruvate in the presence of a base such as sodium bicarbonate in asolvent, such as 2-propanol, 1,4-dioxane, or tetrahydrofuran, thenaffords imidazole 4. Subsequent hydrolysis of the ester with, forexample, lithium or sodium hydroxide provides acid VI where R¹⁻⁸ aredescribed above.

Intermediates VII may be prepared as illustrated in Scheme 2 fromintermediates 5 and 6.Intermediates 5, wherein L is a suitable nitrogen protecting group, suchas tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and trityl (Tr),are either commercially available or known in the literature.Intermediates 6, wherein X is Cl, Br, I, or triflate and R² is asdefined above, are either commercially available, known in theliterature, or prepared by a variety of methods familiar to thoseskilled in the art. Intermediates 7 may be prepared by heating 5 and 6together in the presence of a base such as triethylamine orN,N-diisopropylethylamine in solvents such as toluene,N,N-dimethylformamide, or ethylene glycol dimethyl ether according toprocedures outlined in L. Toma, et. al. J. Med. Chem. 2002, 45,4011-4017 and references contained therein. Alternatively, Intermediates7 may also be prepared by heating 5 and 6 together in the presence of abase such as sodium tert-butoxide, potassium phosphate, or cesiumcarbonate, in a solvent such as toluene, 1,4-dioxane, or tetrahydrofuranwith catalytic amounts of a palladium II source and a trisubstitutedphosphine according to procedures outlined in J. P. Wolfe, et. al. J.Org. Chem. 2000, 65, 1144 and J. P. Wolfe, et. al. J. Org. Chem. 2000,65, 1158. After coupling, racemic Intermediates 7 can be resolved intothe pure enantiomers by using chiral chromatography with, for example, achiralcel AD column or chiralcel OD column using solvent mixturescomprised of ethanol/hexane or 2-propanol/heptane. The L protectinggroup of 7 is then removed with, for example, trifluoroacetic acid ormethanolic hydrogen chloride in the case of Boc to give the desiredamine intermediate VII, where R⁹ and R¹⁰ are described above.

Compound Ia may be prepared as illustrated in Scheme 3 fromintermediates VI and VII. Intermediates VI and VII are coupled understandard peptide coupling conditions, for example, using1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazoleor O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate and 1-hydroxy-7-azabenzotriazole in the presence ofa base such as N,N-diisopropylethylamine or triethylamine in a solventsuch as N,N-dimethylformamide or dichloromethane for 3 to 48 hours atambient temperature to provide compound Ia where R¹ to R¹⁰ are describedabove. The product is purified from unwanted side products, ifnecessary, by recrystallization, trituration, preparative thin layerchromatography, flash chromatography on silica gel, such as with aBiotage® apparatus, or HPLC. Compounds that are purified by HPLC may beisolated as the corresponding salt. Purification of intermediates isachieved in the same manner.

Intermediate VIII may be prepared as illustrated in Scheme 4 fromintermediates 8 and 9. Intermediate 8, wherein L is a suitable nitrogenprotecting group, such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl(Cbz), and trityl (Tr), is either commercially available, known in theliterature, or prepared by a variety of methods familiar to thoseskilled in the art. Intermediate 9 wherein X is Cl, Br, I, or triflateand R¹⁰ is as defined above, is either commercially available, known inthe literature, or prepared by a variety of methods familiar to thoseskilled in the art. Intermediate 10 may be prepared by heating 8 and 9together in the presence of a base such as lithium dicyclohexylamide orlithium diisopropylamide, in a solvent such as toluene with catalyticamounts of a palladium II source and a trisubstituted phosphine such astri tert-butylphosphine according to procedures outlined in M.Jorgensen, et. al. J. Am. Chem. Soc. 2002, 124, 12557. After coupling,the L protecting group of Intermediate 10 is removed with, for example,trifluoroacetic acid or methanolic hydrogen chloride in the case of Bocto give the desired amine intermediate VIII, where R¹⁰ is describedabove.

Compounds Ib and Ic may be prepared as illustrated in Scheme 5 fromintermediates VI and VIII described above. Intermediates VI and VII arecoupled under standard peptide coupling conditions, for example, usingmethanesulphonyl chloride in the presence of a base such asN-methylimidazole in a solvent such as dichloromethane for 1 to 18 hoursat ambient temperature to provide compound Ib. Compound Ib may then behydrolyzed using, for example, potassium trimethylsilanolate in asolvent such as tetrahydrofuran to afford compound Ic where R¹ to R¹⁰are described above. The compound Ic is purified from unwanted sideproducts, if necessary, using the methods described above in Scheme 3.Compounds that are purified by HPLC may be isolated as the correspondingsalt. Purification of intermediates is achieved in the same manner.

An additional route to product Id is illustrated in Scheme 6.Intermediate 11 wherein L is a suitable nitrogen protecting group suchas tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and trityl (Tr)are either commercially available or known in the literature.Intermediates VI and 11 are coupled under standard peptide couplingconditions, for example, using methanesulfonyl chloride in the presenceof a base such as N-methylimidazole in a solvent such asN,N-dimethylformamide (DMF) or dichloromethane for 1 to 8 hours atambient temperature to provide compound 12 (Ueki, H.; et. al. J. Org.Chem. 2003, 68, 7104). Next, the methyl ester is reduced using, forexample, lithium borohydride in a solvent such as methanol or ethanol toafford alcohol 13. The alcohol 13 can then be protected with, forexample, an acetate group by treatment of 13 with acetic anhydride in asolvent such as dichloromethane and a base such as4-(dimethylamino)-pyridine (DMAP). The nitrogen protecting group of 14is then removed with, for example, palladium on carbon under a hydrogenatmosphere in methanol in the case of L=Cbz to give the desired amine15. Compound Id may then be prepared by heating amine 15 and R¹⁰X (6)together in the presence of a base such as sodium tert-butoxide,potassium phosphate, or cesium carbonate in a solvent such as toluene,1,4-dioxane, or tetrahydrofuran with catalytic amounts of a palladium IIsource and a trisubstituted phosphine according to procedures outlinedin J. P. Wolfe, et. al. J. Org. Chem. 2000, 65, 1144 and J. P. Wolfe,et. al. J. Org. Chem. 2000, 65, 1158. The acetate protecting group isthen removed with, for example, sodium methoxide in a solvent such astetrahydrofuran to give the desired alcohol compound Id. The product ispurified from unwanted side products, if necessary, using the methodsdescribed above in Scheme 3. Compounds that are purified by HPLC may beisolated as the corresponding salt. Purification of intermediates isachieved in the same manner.

In some cases the products Ia, Ib, Ic, and Id or the syntheticintermediates illustrated in the above schemes may be further modified,for example, by manipulation of substituents on R⁹ or R¹⁰. Thesemanipulations may include, but are not limited to, reduction, oxidation,alkylation, arylation, condensation, acylation, rearrangement,protection, deprotection, substitution, and hydrolysis reactions thatare commonly known to those skilled in the art. One such example isillustrated in Scheme 7. Hydrolysis of ester 16 with, for example,lithium or sodium hydroxide provides acid Ie. Further manipulation of Iewas achieved by condensation with amines, under standard peptidecoupling conditions, for example, using1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazoleor O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate and 1-hydroxy-7-azabenzotriazole in the presence ofa base such as N,N-diisopropylethylamine or triethylamine in a solventsuch as N,N-dimethylformamide or dichloromethane for 3 to 48 hours atambient temperature to provide compound If.

Another example of further reactions that may lead to products Ig isillustrated in Scheme 8. Intermediate 17 can be converted to azide 18 byfirst converting the alcohol to the corresponding mesylate using, forexample, methanesulphonyl chloride with N,N-iisopropylethylamine andthen treatment of the mesylate with, for example, sodium azide. Theazide can then be reduced to the corresponding amine 19 using, forexample, hydrogen gas in the presence of a palladium catalyst. Amine 19can be acylated with, for example, an acid chloride 20 to give amide 21.The methyl ester of 21 can then be hydrolyzed using, for example,lithium or sodium hydroxide in water and tetrahydrofuran to givecompound Ig. Amine 19 is a useful intermediate in that it may beacylated with carboxylic acids using, for example, EDC and HOBt or otherstandard coupling conditions to afford amide 21. Alternatively, amine 19may be converted to sulphonamides or ureas using standard chemistry viaa variety of methods known, to those skilled in the art.

Another example of further reactions that can lead to products Ih isillustrated in Scheme 9. Piperidine intermediate 22 is synthesizedaccording to methods in Scheme 4 using starting materials that arereadily synthesized via a number of methods known to those skilled inthe art. Hydrolysis of the methyl ester of 22 to the corresponding acidfollowed by Curtius rearrangement of the acid and subsequent trapping ofthe isocyanate intermediate with benzyl alcohol affords theN-carboxybenzyl protected amine 23. The silyl protecting group of 23 maythen be removed with, for example, tetrabutylammonium fluoride and theresulting alcohol is oxidized using Dess-Martin's periodinane. Thisalchohol is further oxidized the corresponding acid using sodiumchlorite and the acid is then converted to methyl ester 24. Deprotectionof the piperazine nitrogen of 24 is achieved using, for example,trifluoroacetic acid in dichloromethane and the resulting amine is thencoupled to acid VI using standard amide bond coupling conditions such asEDC with HOBt to afford compound 25. Deprotection of the N-carboxybenzylgroup of 25 to afford the primary amine 26 is then achieved using, forexample, hydrogen gas in the presence of a catalyst such as palladiumhydroxide or palladium on carbon in a solvent such as methanol.Acylation of amine 26 with acid 27 can then be achieved using standardamide bond forming reaction conditions such as EDC with HOBt in thepresence of a base such as N,N-diisopropylethylamine in a solvent suchas N,N-dimethylformamide or dichloromethane. The resulting coupledcompound is then converted to the desired acid 1h via treatment with,for example, potassium trimethylsilanolate or aqueous lithium hydroxidein solvents such as tetrahydrofuran.

Yet another example of further reactions that may lead to products suchas Ii is illustrated in Scheme 10. Piperidine 28 can be synthesized viaa number of methods known to those skilled in the art. The ester ofpiperidine 28 can be converted to aldehyde 29 by removal of thetert-butyl group from the ester followed by treatment of thecorresponding acid with borane in tetrahydrofuran. The resultingaldehyde 29 can then be homologated using any of a number of methodsknown to those skilled in the art. One such method involves treatment ofaldehyde 29 with a Horner Emmons phosphonate reagent in the presence ofa base such as n-butyl lithium in a solvent such as tetrahydrofuran.Hydrogenation of the resulting olefin also results in deprotection ofthe piperazine nitrogen to afford intermediate 30. Compound 30 can thenbe coupled to intermediate VI and the methyl ester hydrolyzed to thecorresponding carboxylic acid Ii using standard procedures described inthe above schemes.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way.

Intermediate 11-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylic acid

Step A: N-(3-Ethoxyphenyl)-4-methylbenzenecarboxamidine To a solution of2.2 ml (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodiumbis(trimethylsilyl)amide in 5.0 mL of tetrahydrofuran at ambienttemperature was added 0.52 mL (4.0 mmol) of 3-ethoxyaniline and theresulting solution was stirred for 20 min. To this reaction mixture wasslowly added a solution of 0.47 g (4.0 mmol) of p-tolunitrile in 2.0 mLof tetrahydrofuran. The resulting mixture was stirred at ambienttemperature for 5 hrs and then poured into brine (25 mL) anddichloromethane (50 mL). The organic layer was separated, and theaqueous layer was extracted with dichloromethane (25 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedin vacuo to yield the title compound as yellow solid, which was usedwithout further purification. LC/MS 255.2 (M+1).Step B: Ethyl1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylate To amixture of 1.1 g (4.0 mmol) of the compound from Step A and 0.80 g (9.5mmol) of sodium bicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL(4.8 mmol) of ethyl bromopyruvate. The reaction mixture was refluxedovernight. After cooling to room temperature, the solid was filtered offand the filtrate was concentrated in vacuo. Flash chromatography on aBiotage Horizon® system (silica gel, 5 to 40% ethyl acetate in hexanesgradient then 40% ethyl acetate in hexanes) gave the title compound as ayellow oil. LC/MS 351.2 (M+1).Step C: 1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylicacid To a solution of 0.75 g (2.1 mmol) of ethyl1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylate fromStep B in 10 mL of tetrahydrofuran, 5 mL of water and 5 mL of methanolwas added 0.80 mL (4.0 mmol) of 5.0 M NaOH solution. The reactionmixture was stirred at ambient temperature overnight. Then hydrochloricacid (2.0 M) was added to neutralize the reaction mixture. After removalof the organic solvents in vacuo, dichloromethane (20 mL) was added andthe organic layer was separated. The aqueous layer was extracted withdichloromethane (10 mL), and the combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo to yield the titlecompound as a yellow foam. LC/MS 323.3 (M+1).

Intermediate 21-(3-Ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazole-4-carboxylicacid

Step A: N-(3-Ethoxyphenyl)-2-fluoro-4-methylbenzenecarboximidamide To asolution of 2.2 ml (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodiumbis(trimethylsilyl)amide in 10 mL of tetrahydrofuran at ambienttemperature was added 0.52 mL (4.0 mmol) of 3-ethoxyaniline and theresulting solution was stirred for 20 min. To this reaction mixture wasadded 0.54 g (4.0 mmol) of 4-fluoro-4-methylbenzonitrile. The resultingmixture was stirred at ambient temperature for 3 hrs and then pouredinto brine (25 mL) and dichloromethane (50 mL). The organic layer wasseparated and the aqueous layer was extracted with dichloromethane (25mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated in vacuo to yield the title compound as a palegreen solid which was used without further purification. LC/MS 273.2(M+1).Step B: Ethyl1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazole-4-carboxylateTo a mixture of the compound from Step A and 0.80 g (9.5 mmol) of sodiumbicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) ofethyl bromopyruvate. The reaction mixture was refluxed overnight. Aftercooling to room temperature, the solid was filtered off and the filtratewas concentrated in vacuo. Flash chromatography on a Biotage Horizon®system (silica gel, 0 to 50% ethyl acetate in hexanes gradient) gave thetitle compound as a viscous yellow oil. LC/MS 369.2 (M+1).Step C:1-(3-Ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazole-4-carboxylicacid To a solution of 0.81 g (2.2 mmol) of ethyl1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazole-4-carboxylatefrom Step B in 10 mL of tetrahydrofuran, 5 mL of water and 5 mL ofmethanol was added 1.0 mL (5.0 mmol) of 5.0 M NaOH solution. Thereaction mixture was stirred at ambient temperature overnight.Hydrochloric acid (2.0 M) was then added to neutralize the reactionmixture. After removal of the organic solvents in vacuo, dichloromethane(20 mL) was added and the organic layer was separated. The aqueous layerwas extracted with dichloromethane (10 mL), and the combined organiclayers were dried over sodium sulfate, filtered and concentrated invacuo to yield the title compound as a yellow foam. LC/MS 341.1 (M+1).

Intermediate 3 Methyl 4-(3-quinolinyl)-2-piperazinecarboxylate,trifluoroacetic acid salt

Step A: 1-tert-Butyl 2-methyl4-quinolin-3-ylpiperazine-1,2-dicarboxylate To a solution of 3.50 g(14.3 mmol) 1-tert-butyl 2-methyl piperazine-1,2-dicarboxylate in 150 mLanhydrous toluene was added 1.62 mL (11.9 mmol) of 3-bromoquinoline. Theresulting solution was purged with nitrogen gas for 15 min, and thenpurged under vacuum for 5 min. Next, 1.59 g (17.6 mmol) of sodiumtert-butoxide was added, and the system was again purged for 2 min undervacuum. To this solution were added 444 mg (0.714 mmol) of(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene and 342 mg (0.595mmol) of bis(dibenzylideneacetone)palladium, and the system was purgedone last time for 2 min under vacuum. The mixture was then heated undernitrogen to 95° C. for 3.5 h, taken up in anhydrous diethyl ether, andfiltered through a plug of Celite®. The filtrate was concentrated invacuo to yield a red solid, which was purified using a Biotage Horizon®system (30% ethyl acetate/hexanes mixture) to give the title compound asa racemic mixture. Chiral HPLC separation (Chiralcel AD, 60%2-propanol/heptane) afforded the R enantiomer (first eluting) and the Senantiomer (second eluting), each in ≧99% ee. For the S enantiomer, ¹HNMR (CDCl₃): δ 8.75 (d, J=2.1 Hz, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.68 (dd,J=6.9, 1.1 Hz, 1H), 7.53 (ddd, J=8.7, 7.1, 1.6 Hz, 1H), 7.48 (td, J=8.2,1.3 Hz, 1H) 7.36 (d, J=2.5 Hz, 1H), 4.96 (s, 0.55H) 4.78 (s, 0.45H),4.11 (d, J=7.1, 0.55H), 4.01 (d, J=13.0 Hz, 0.45H), 3.80 (d, J=8.0 Hz,3H), 3.57 (m, 1H), 3.44 (t, J=9.4 Hz, 0.55H), 3.32 (t, J=9.6 Hz, 0.45H),3.04 (m, 1H), 2.89 (q, J=8.6 Hz, 1H) 1.52 (s, 5H), 1.48 (s, 4H). LC/MS372.3 (M+1).Step B: Methyl 4-(3-quinolinyl)-2-piperazinecarboxylate, trifluoroaceticacid salt To 1.16 g (3.12 mmol) of the S enantiomer from Step A wasadded 30 mL dichloromethane and 3 mL trifluoroacetic acid. When thereaction was complete by LC-MS (18 h), the solution was concentrated invacuo and triturated with ethyl ether and filtered to give the titlecompound as a yellow solid. ¹H NMR (CD₃OD): δ 9.1 (d, J=2.7 Hz, 1H),8.37 (d, J=2.5 Hz, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.84 (ddd, J=8.3, 7.1,1.2 Hz, 1H), 7.77 (t, J=7.5 Hz, 1H), 4.57 (dd, J=9.1, 3.7 Hz, 1H), 4.21(dd, J=9.8, 3.7 Hz, 1H) 3.92 (t, J=9.5 Hz, 1H), 3.92 (s, 3H), 3.66 (m,2H), 3.47 (m, 2H). LC/MS 272.3 (M+1).

Intermediate 4((2R)-1-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-piperazin-2-yl)methylacetate

Step A: 1-Benzyl 3-methyl(3R)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazine-1,3-dicarboxylateTo a solution of 3.18 g (9.88 mmol) of Intermediate 1 in 75 mL ofanhydrous dichloromethane at 0° C. was added 1.5 mL (19 mmol) of1-methylimidazole followed by 0.80 mL (9.9 mmol) of methanesulfonylchloride. The resulting mixture was stirred with gradual warming toambient temperature over 20 min, then re-cooled to 0° C. A solution of2.39 g (8.59 mmol) of 1-benzyl3-methyl-(3R)-piperazine-1,3-dicarboxylate in 25 mL of anhydrousdichloromethane was then added and the reaction mixture was allowed towarm to ambient temperature over 1 h. The reaction was then quenchedwith a saturated aqueous ammonium chloride solution (25 mL) and thelayers were separated. The aqueous layer was extracted withdichloromethane (2×100 mL) and the combined organic layers were washedwith brine (50 mL), dried over magnesium sulfate, filtered andconcentrated in vacuo. The crude residue was purified on a Biotage®purification apparatus (silica gel, 40 to 50% ethyl acetate in hexanesgradient) to yield the title compound as a colorless solid. LC/MS 583.5(M+1).Step B: Benzyl(3R)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl-3-(hydroxymethyl)piperazine-1-carboxylateTo a solution of 4.10 g (7.04 mmol) of 1-benzyl 3-methyl(3R)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazine-1,3-dicarboxylatefrom Step A in 75 mL of anhydrous methanol at 0° C. under a nitrogenatmosphere was added 460 mg (21.1 mmol) of lithium borohydride. Anadditional 460 mg (21.1 mmol) of lithium borohydride was added to thereaction mixture every hour for 3 hours and stirred for one hour afterthe final addition. The reaction was quenched with a saturated aqueousammonium chloride solution (50 mL) followed by concentration in vacuo toremove the methanol. The residue was diluted with water (15 mL) andextracted with dichloromethane (2×75 mL). The combined organic layerswere washed with brine (50 mL), dried over magnesium sulfate, filteredand concentrated in vacuo. The crude residue was purified on a Biotage®purification apparatus (silica gel, 65% ethyl acetate in hexanes) toyield the title compound as a colorless solid. LC/MS 555.2 (M+1).Step, C: Benzyl(3R)-3-[(acetyloxy)methyl]-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylateTo a stirred solution of 3.40 g (6.13 mmol) of benzyl(3R)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-(hydroxymethyl)-piperazine-1-carboxylatefrom Step B in 60 mL of anhydrous dichloromethane was added 2.30 mL(13.4 mmol) of N,N-diisopropylethylamine, 1.20 ml (12.2 mmol) of aceticanhydride and 4.0 mg (0.30 mmol) of 4-(dimethylamino)-pyridine. Theresulting solution was stirred at ambient temperature overnight,quenched with a saturated aqueous ammonium chloride solution (20 mL).The aqueous layer was separated and extracted with dichloromethane (2×75mL), and the combined organic layers were washed with brine (50 mL),dried over magnesium sulfate, filtered and concentrated in vacuo. Theresulting crude residue was purified on a Biotage® purificationapparatus (silica gel, 50 to 75% ethyl acetate in hexanes gradient) toyield the title compound as a colorless foam. LC/MS 597.2 (M+1).Step D:((2R)-1-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl-1H-imidazol-4-yl]carbonyl}piperazin-2-yl)methylacetate To 350 mg (0.330 mmol) of 10% palladium on carbon was added asolution of 3.55 g (5.95 mmol) of benzyl(3R)-3-[(acetyloxy)methyl]-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylatefrom Step C in 50 mL of anhydrous methanol. The resulting suspension wasagitated under an atmosphere of hydrogen at 40 psi for 2 hours thenfiltered through a plug of Celite®. The plug was washed with methanol(75 mL), and the combined filtrates were concentrated in vacuo to yieldthe title compound as a colorless foam, which was used without furtherpurification. ¹H NMR (DMSO-d₆): δ 7.85 (s, 1H), 7.33 (t, J=8.2 Hz, 1H),7.21 (d, J=8.5 Hz, 2H), 7.13 (d, J=8.5 Hz, 2H), 6.98-7.00 (m, 1H), 6.92(s, 1H), 6.77-6.79 (m, 1H), 4.68-5.81 (m, 2H), 4.18-4.59 (m, 3H), 4.00(q, J=6.8 Hz, 2H), 2.72-3.02 (m, 4H), 2.57-2.62 (m, 1H), 2.27 (s, 3H),1.78-2.00 (m, 3H), 1.27 (t, J=6.8 Hz, 3H). LC/MS 463.5 (M+1).

Intermediate 5 Methyl 3-bromo-1-naphthoate

Step A: Methyl 3-nitro-1-naphthoate To a suspension of 22.0 g (0.101mol) of 3-nitro-1-napthalene-carboxylic acid prepared according toprocedures in Duffy, K. J., et al., in J. Med. Chem. 2001, 44,3730-3745) in 1 L of anhydrous dichloromethane at 0° C. under anatmosphere of nitrogen was added 9.8 mL (0.11 mol) of oxalyl chloridefollowed by 0.80 mL (10 mmol) of anhydrous N,N-dimethylformamide. Thereaction mixture was allowed to gradually warm to ambient temperaturefor 3 h until gas evolution ceased, and the resulting homogeneoussolution was concentrated in vacuo to remove all volatiles. The residuewas then dissolved in 1 L of anhydrous dichloromethane and 20 mL (0.51mol) of anhydrous methanol was added. After stirring for 1 h, thereaction was carefully quenched with a saturated aqueous sodiumbicarbonate solution (500 mL). The organic layer was separated and theaqueous layer was extracted with dichloromethane (2×250 mL). Thecombined organic layers were washed with brine (300 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo to yield the titlecompound as a pale yellow solid which was used without furtherpurification. LC/MS 232.2 (M+1).Step B: Methyl 3-amino-1-naphthoate To 1.15 g (1.08 mmol) of 10%palladium on carbon was added a suspension of 11.6 g (50.0 mmol) ofmethyl 3-nitro-1-naphthoate from Step A in 150 mL of anhydrous ethanoland 40 ml of anhydrous dichloromethane. The resulting suspension wasagitated under an atmosphere of hydrogen at 40 psi for 3 h during whichtime all solids dissolved. The reaction mixture was filtered through aplug of Celite®, which was subsequently washed with dichloromethane (300mL). The combined filtrates were concentrated in vacuo to yield thetitle compound as a pale green gum, which was used without furtherpurification. LC/MS 202.1 (M+1).Step C: Methyl 3-bromo-1-naphthoate A solution of 4.34 g (62.9 mmol) ofsodium nitrite in 40 mL of water was added dropwise to a 0° C. solutionof 11.5 g (57.2 mmol) of methyl 3-amino-1-naphthoate from Step B in 300mL of ethanol and 60 mL of 48% aqueous hydrobromic acid whilemaintaining an internal reaction temperature below 10° C. The resultingdark red reaction mixture was stirred at 0° C. for an additional 30 min.The cooled (0° C.) reaction mixture was then added over 20 min to asuspension of 8.21 g (57.2 mmol) of cuprous bromide in 60 mL of ethanoland 60 mL of 48% aqueous hydrobromic acid heated to 95° C. Afterstirring for 30 min the reaction mixture was cooled to 0° C. andcarefully partitioned between ethyl ether (250 mL) and water (600 mL).The organic layer was separated and the aqueous layer was extracted withethyl ether (2×300 mL). The combined organic layers were washed withbrine (100 mL), dried over magnesium sulfate, filtered and concentratedin vacuo. The residue was passed through a plug of silica gel elutingwith 30% dichloromethane in hexanes and the filtrate concentrated invacuo. Flash chromatography on a Biotage® purification apparatus (silicagel, 7% dichloromethane/hexanes) yielded the title compound as acolorless solid. ¹H NMR (DMSO-d₆): δ 8.67 (d, J=8.4 Hz, 1H), 8.50 (s,1H), 8.15 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.68-7.71 (m, 1H), 7.63-7.66(t, J=7.6 Hz, 1H), 3.94 (s, 3H). LC/MS 265.0 (M+1) and 267.0 (M+3).

Intermediate 6 Methyl3-{(3S)-3-[(isoprolylamino)carbonyl]-1-piperazinyl}-1-naphthoate

Step A: 4-Benzyl 1-tert-butyl2-[(isopropylamino)carbonyl]piperazine-1,4-dicarboxylate To 200 mg(0.549 mmol) of4-[(benzoyloxy)carbonyl]-1-(tert-butoxycarbonyl)piperazine-2-carboxylicacid in 5 mL of anhydrous dichloromethane at 0° C. was added 0.042 mL(0.55 mmol) of methanesulfonyl chloride and 0.110 mL (1.37 mmol)1-methylimidazole. The reaction was allowed to stir under nitrogen for30 min prior to the addition of 0.042 mL (0.49 mmol) of isopropylamine,and the reaction mixture was next allowed to warm to room temperature.The mixture was then poured into saturated sodium bicarbonate (10 mL)and extracted with dichloromethane (2×5 mL). The combined organic layerswere washed with brine (10 mL) and dried with magnesium sulfate. Themixture was concentrated in vacuo to give a yellow oil, and carriedforward without purification. LC/MS 406.2 (M+1).Step B: tert-Butyl 2-[(isopropylamino)carbonyl]piperazine-1-carboxylateTo 220 mg (0.54 mmol) of the product from Step A was added 15 mLmethanol and nitrogen was bubbled through the solution for 15 min. Next,40 mg of palladium (10% on carbon) was added, and the system was againpurged with nitrogen. Next, the flask was carefully purged with hydrogenand the reaction mixture was allowed to stir for 45 min at roomtemperature under 1 atm of hydrogen gas until the reaction was completeby LC-MS. After purging the system with nitrogen, the solution wascarefully filtered through a Celite® plug to remove the palladium andthen rinsed with methanol (100 mL), and the filtrate was concentrated invacuo to yield a pale yellow solid. ¹H NMR (DMSO-d₆): δ 4.35 (br s, 1H),4.00 (q, J=6.4 Hz, 1H), 3.77 (d, J=3.0 Hz, 1H), 3.72 (s, 1H), 3.23 (dt,J=9.3 Hz, 3.0 Hz, 1H), 2.92 (br, 1H), 2.86 (d, J=10 Hz, 1H), 2.63 (t,J=11.2 Hz, 1H), 1.45 (s, 9H), 1.17 (m, 6H). LC/MS 272.1 (M+1).Step C: tert-Butyl(2S)-2-[(isopropylamino)carbonyl]-4-[4-methoxycarbonyl)-2-naphthyl]piperazine-1-carboxylateTo 162 mg (0.597 mmol) of the compound from step B and 191 mg (0.597mmol) of Intermediate 5 was added 6 mL anhydrous 1,4-dioxane. The systemwas purged for 5 min and then flushed with nitrogen. Next, 291 mg (0.895mmol) of cesium carbonate was added to the flask, and the system wasagain purged for 5 min with nitrogen, and then flushed with nitrogen.Next, 28 mg (0.070 mmol) of2-dicyclohexylphosphino-2′(N,N-dimethylamino)biphenyl, and 7 mg (0.01mmol) of bis(dibenzylideneacetone)palladium were added, and the systemwas again purged with nitrogen. Finally the reaction mixture was heatedat 85° C. under nitrogen for 24 h. After cooling to room temperature,the solution was filtered through Celite® and concentrated in vacuo toyield an orange oil, which was purified using a Biotage Horizon® system(15%-40% ethyl acetate in hexanes gradient) to give the title compoundas a racemic mixture. Chiral HPLC separation (Chiralcel AD, 20%2-propanol/heptane) afforded the R enantiomer (first eluting) and the Senantiomer (second eluting), each in ≧99% ee. For the S enantiomer: ¹HNMR (CD₃OD): δ 8.63 (d, J=8.7 Hz, 1H), 7.91 (s, 1H), 7.88 (d, J=8.0 Hz,1H), 7.76 (d, J=8.0 Hz, 1H), 7.42 (t, J=5.5 Hz, 1H), 7.37 (t, J=7.4 Hz,2H), 4.56 (s, br, 2H), 4.20 (br, 1H), 3.99 (m, 2H), 3.96 (s, 3H), 3.67(br, 1H), 3.60 (t, J=2.9 Hz, 1H), 3.19 (br, 2H), 2.94 (s, 1H), 1.48 (s,9H), 1.16 (d, J=6.6 Hz, 6H). LC/MS 456.1 (M+1).Step D: Methyl3-{(3S)-3-[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoate To 96mg (0.21 mmol) of the S enantiomer from Step C was added 5 mLdichloromethane and 0.5 mL trifluoroacetic acid. When the reaction wascomplete by LC-MS (1 h), the solution was concentrated in vacuo. Thereddish oil was next triturated with ethyl ether (3 mL), and filtered togive the title compound as a beige solid. LC/MS 356.1 (M+1).

Intermediate 7 [(3-Bromo-1-naphthyl)methoxy](triisopropyl)silane

Step A: (3-Bromo-1-naphthyl)methanol To a solution of 5.10 g (19.2 mmol)of Intermediate 5 in 20 mL of anhydrous tetrahydrofuran at −78° C. underan atmosphere of nitrogen was added 48 mL (48 mmol) of a 1.0 M solutionof diisobutylaluminum hydride in toluene. The resulting solution wasallowed to gradually warm to 0° C. over 90 min and quenched with asaturated aqueous solution of potassium sodium tartrate (25 mL). Theresulting suspension was vigorously stirred with gradual warming toambient temperature over 2 h and the layers separated. The aqueous layerwas extracted with ethyl acetate (3×20 mL) and the combined organiclayers were washed with brine (30 mL), dried over magnesium sulfate,filtered and concentrated in vacuo to afford the title compound as awhite solid which was used without further purification LC/MS 237.0(M+1) and 239.0 (M+3).Step B: [(3-Bromo-1-naphthyl)methoxy](triisopropyl)silane To a solutionof 4.56 g (19.2 mmol) of (3-bromo-1-naphthyl)methanol from Step A in 10mL of anhydrous N,N-dimethylformamide was added 2.88 g (42.3 mmol) ofimidazole, 117 mg (0.962 mmol) of 4-(dimethylamino)pyridine and 4.5 mL(21 mmol) of triisopropylsilyl chloride. The resulting solution wasstirred at ambient temperature for 15 h, diluted with a saturatedaqueous ammonium chloride solution (100 mL) and extracted with ether(3×40 mL). The combined organic layers were washed with water (2×30 mL)then brine (25 mL), dried over magnesium sulfate, filtered andconcentrated in vacuo. The crude residue was purified on a Biotage®purification apparatus (silica gel, 3% methylene chloride in hexanes) toyield Intermediate 7 as a colorless oil. ¹H NMR (CDCl₃): δ 7.92-7.91 (m,1H), 7.89-7.86 (m, 1H), 7.78-7.75 (m, 2H), 7.52-7.48 (m, 2H), 5.27 (s,2H), 1.28-1.21 (m, 3H), 1.13 (d, J=7.4 Hz, 18H). LC/MS 393.0 (M+1) and395.0 (M+3).

Intermediate 81-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylicacid

Step A:N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-fluorobenzenecarboxamidine To asolution of 2.39 g (15.8 mmol) of 1,4-benzodioxan-6-amine in 30 mL oftetrahydrofuran at ambient temperature was added 8.7 ml (17.4 mmol) of2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide and theresulting solution was stirred for 20 min. To this reaction mixture wasadded 1.91 g (15.8 mmol) of 4-fluorobenzonitrile all at once. Theresulting mixture was stirred at ambient temperature overnight and thenpoured into brine (50 mL) and dichloromethane (150 mL). The organiclayer was separated and the aqueous layer was extracted withdichloromethane (50 mL). The combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo to yield the titlecompound as yellow solid, which was used without further purification.LC/MS 273.2 (M+1).Step B: Ethyl1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylateTo a mixture of the product from Step A and 4.0 g (48 mmol) of sodiumbicarbonate in 50 mL of 1,4-dioxane was added 3.0 mL (24 mmol) of ethylbromopyruvate. The reaction mixture was refluxed overnight. Aftercooling to room temperature, the solid was filtered off and the filtratewas concentrated in vacuo. Flash chromatography on a Biotage Horizon®system (silica gel, 0 to 50% ethyl acetate in hexanes gradient) gave thetitle compound as a yellow solid. LC/MS 369.1 (M+1).Step C:1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylicacid To a solution of 2.1 g (5.7 mmol) of ethyl1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylatein 20 mL of tetrahydrofuran, 10 mL of water and 10 mL of methanol wasadded 2.0 mL (10 mmol) of 5.0 M NaOH solution. The reaction mixture wasstirred at ambient temperature overnight. Hydrochloric acid (2.0 M) wasthen added to neutralize the reaction mixture. After removal of theorganic solvents in vacuo, dichloromethane (20 mL) was added and theorganic layer was separated. The aqueous layer was extracted withdichloromethane (10 mL), and the combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo to yield the titlecompound as a pale yellow foam. LC/MS 341.0 (M+1).

Intermediate 9 1-Benzyl 4-tert-butyl4-(2-naphthyl)piperidine-1,4-dicarboxylate

Step A: tert-Butyl 2-naphthylacetate To a solution of 5.0 g (26.9 mmol)of 2-napthylacetic acid in 75 mL of dichloromethane was added 2.60 mL(29.5 mmol) of oxalyl chloride followed by 0.20 mL (2.7 mmol) ofN,N-dimethylformamide. The resulting solution was stirred at ambienttemperature for 1 h and then all volatiles were removed in vacuo. Theresulting residue was dissolved in 15 mL of dichloromethane and 15 mL of2-methyl-2-propanol, and the resulting solution was stirred for 2.5 h.All volatiles were removed in vacuo and the crude residue was purifiedon a Biotage® purification apparatus (silica gel, 7% ethyl acetate inhexanes) to afford the title compound as a colorless oil. LC/MS 243.1(M+1).Step B: 1-Benzyl 4-tert-butyl 4-(2-naphthyl)piperidine-1,4-dicarboxylateTo a suspension of 695 mg (17.4 mmol) of a 60% dispersion of sodiumhydride in mineral oil in 4 mL of anhydrous N,N-dimethylformamide at 0°C. under an atmosphere of nitrogen was added a solution of 2.0 g (7.2mmol) of benzyl bis(2-chloroethyl)carbamate in 5 mL of anhydrousN,N-dimethylformamide, followed by a solution of 1.9 g (8.0 mmol) oftert-butyl 2-naphthylacetate from Step A in 5 mL of anhydrousN,N-dimethylformamide. The resulting mixture was stirred with gradualwarming to ambient temperature over 1 h. A solution of 134 mg (0.362mmol) of tetrabutylammonium iodide in 1 mL of anhydrousN,N-dimethylformamide was added to the mixture, and the resulting orangesuspension was heated at 70° C. for 1.5 h. After cooling to ambienttemperature the reaction was quenched with water (100 mL) and extractedwith ethyl acetate (3×25 mL). The combined organic layers were washedwith water (2×20 mL), brine (20 mL), dried over magnesium sulfate,filtered and concentrated in vacuo. The crude residue was purified on aBiotage® purification apparatus (silica gel, 10% acetone in hexanes) toafford the title compound as a yellow oil. ¹H NMR (CDCl₃): δ 7.85-7.76(m, 5H), 7.52-7.45 (m, 3H), 7.38-7.26 (m, 4H), 5.14 (s, 2H), 4.15-4.10(m, 2H), 3.17 (br s, 2H), 2.59 (br s, 2H), 1.92-1.93 (m, 2H), 1.38 (s,9H). LC/MS 446.5 (M+1).

Intermediate 10 Benzyl 4-formyl-4-(2-naphthyl)piperidine-1-carboxylate

Step A: 1-[(Benzyloxy)carbonyl]-4-(2-naphthyl)piperidine-4-carboxylicacid To a solution of 1.60 g (3.59 mmol) of Intermediate 9 in 10 mL ofanhydrous dichloromethane was added 10 mL of trifluoroacetic acid. Theresulting mixture was stirred at ambient temperature for 2 h and thenall volatiles were removed in vacuo. The resulting residue was dissolvedin 15 mL of anhydrous toluene and all volatiles were again removed invacuo to afford the title compound as a white solid. LC/MS 390.2 (M+1).Step B: Benzyl 4-formyl-4-(2-naphthyl)piperidine-1-carboxylate To asolution of 1.45 g (3.72 mmol) of the above1-[(benzyloxy)carbonyl]-4-(2-naphthyl)piperidine-4-carboxylic acid fromStep A in 25 mL of anhydrous tetrahydrofuran at 0° C. was added 3.7 mL(3.7 mmol) of a 1.0 M solution of borane-tetrahydrofuran complex intetrahydrofuran. The resulting mixture was stirred with gradual warmingto ambient temperature over 12 h, re-cooled to 0° C., and quenched with0.75 mL (18 mmol) of methanol. The mixture was diluted with water (25mL) and extracted with ethyl acetate (3×10 mL). The combined organiclayers were washed with water (10 mL), brine (10 mL), dried overmagnesium sulfate, filtered and evaporated in vacuo. The crude residuewas purified on a Biotage® purification apparatus (silica gel, 10-60%ethyl acetate in hexanes gradient) to afford the title compound as awhite solid. ¹H NMR (CDCl₃): δ 9.48 (s, 1H), 7.86 (d, J=8.7 Hz, 1H),7.84-7.82 (m, 2H), 7.74 (s, 1H), 7.52-7.50 (m, 2H), 7.38-7.26 (m, 6H),5.14 (s, 2H), 4.00 (br s, 2H), 3.26 (br s, 2H), 2.51-2.49 (m, 2H),2.17-2.10 (m, 2H). LC/MS 396.1 (M+Na).

Example 1(2S)-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(3-quinolinyl)-2-piperazinecarboxylicacid, trifluoroacetic acid salt

Step A: Methyl(2S)-1-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-quinolin-3-ylpiperazine-2-carboxylate,trifluoroacetic acid salt To a solution of 334 mg (1.03 mmol) ofIntermediate 1 and 440 mg (1.14 mmol) of Intermediate 3 (S enantiomer)in 10 mL N,N-dimethylformamide was added 200 mg (1.14 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarboiimide hydrochloride, 153 mg(1.14 mmol) 1-hydroxybenzotriazole, and 0.716 mL (4.12 mmol)N,N-diisopropylethylamine. The solution was allowed to stir at roomtemperature overnight. The reaction was quenched with 0.01%trifluoroacetic acid in water (2.0 mL), and the reaction mixture waspurified directly by reverse phase HPLC (TMC Pro-Pac C18; 30-100% 0.01%trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid in watergradient). The pure fractions were lyophilized overnight to yield ayellow solid. LC-MS 576.2 (M+1).Step B:(2S)-1-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-quinolin-3-ylpiperazine-2-carboxylicacid, trifluoroacetic acid salt To a solution of 52 mg (0.075 mmol) ofthe S enantiomer from Step A in 10 mL of tetrahydrofuran was added 2 mLmethanol and 2 mL 1M lithium hydroxide solution. When the reaction wascomplete by LC-MS (2 h), the solution was partitioned between 1Nhydrochloric acid (10 mL) and ethyl acetate (100 mL). The organic layerwas separated, dried over magnesium sulfate, filtered and concentratedin vacuo to afford a yellow oil. The oil was taken up in acetonitrile (2mL), filtered, and purified by reverse phase HPLC (TMC Pro-Pac C18;30-100% 0.01% trifluoroacetic acid in acetonitrile/0.01% trifluoroaceticacid in water gradient). The pure fractions were lyophilized overnightto give the title compound as a yellow solid. ¹H NMR (CDCl₃): δ 9.26 (s,1H), 8.26 (d, J=7.1 Hz, 1H), 7.87 (s, 1H), 7.83 (m, 2H), 7.67 (m, 2H),7.32 (m, 1H), 7.24 (s, 1H), 7.11 (m, 2H), 6.98 (d, J=7.7 Hz, 1H), 6.80(m, 2H), 5.75 (b, 1H), 4.71 (m, 2H), 4.44 (m, 2H) 3.97 (q, J=6.8 Hz,2H), 3.86 (m, 1H), 3.49-3.35 (m, 4H), 2.32 (s, 3H), 1.38 (t, J=6.8 Hz,3H). LC-MS 562.2 (M+1).

Example 2(2S)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(3-quinolinyl)-2-ethyl-4-(3-quinolinyl)-2-piperazinecarboxamide,trifluoroacetic acid salt

Step A: To a solution of 35 mg (0.062 mmol) of the product of Example 1(S enantiomer) in N,N-dimethylformamide was added 0.187 mL (0.374 mmol)of 2.0 M ethylamine in tetrahydrofuran, 13 mg (0.068 mmol)N-(3-dimethylaminopropyl)-N′-ethylcarboiimide hydrochloride, 9.0 mg(0.068 mmol) 1-hydroxybenzotriazole, and the resulting solution washeated to 35° C. overnight. The solution was quenched with 0.01%trifluoroacetic acid in water (0.5 mL), and purified directly by reversephase HPLC (TMC Pro-Pac C18; 30-100% 0.01% trifluoroacetic acid inacetonitrile/0.01% trifluoroacetic acid in water gradient). Theresulting pure fractions were lyophilized overnight to give the titledcompound as a yellow solid. ¹H NMR (CD₃OD): δ 9.04 (d, J=2.7 Hz, 1H),8.35 (d, J=2.1 Hz, 1H), 8.06 (m, 3H), 7.80 (m, 2H), 7.32 (m, 3H), 7.19(b, 2H), 7.04 (d, J=7.5 Hz, 1H), 6.88 (br, 2H), 6.09 (br, s, 0.5H), 5.28(br, s, 0.5H), 4.59 (m, 1H), 3.97 (m, 4H), 3.54 (br, 1H), 3.39 (br, 1H),3.24 (q, J=7.2 Hz, 2H), 2.33 (s, 3H), 1.32 (t, J=6.8 Hz, 3H), 1.04 (br,3H). LC/MS 589.2 (M+1).

Example 3N-{[(2S)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(3-quinolinyl)-2-piperazinyl]carbonyl}glycine,trifluoroacetic acid salt

Step A: To a mixture of 31 mg (0.049 mmol) of the product Example 1 (Senantiomer), 6.5 mg (0.049 mmol) of glycine, tert-butyl ester, 19 mg(0.10 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarboiimidehydrochloride, and 14 mg (0.10 mmol) of 1-hydroxybenzotriazole in 0.5 mlof N,N-dimethylformamide was added 0.05 ml (0.3 mmol) ofN,N-diisopropylethylamine. After being stirred at ambient temperatureovernight, the reaction was quenched with 1.5 ml of water. Afterfiltration, the unpurified solid product was dissolved in 0.5 ml ofdichloromethane and 0.2 ml of trifluoroacetic acid. The reaction mixturewas stirred at ambient temperature for 3 hours. The volatiles wereremoved under vacuum and the resulting residue was purified by reversephase HPLC (TMC Pro-Pac C18; 30-90% 0.01% trifluoroacetic acid inacetonitrile/0.01% trifluoroacetic acid in water gradient). Theresulting pure fractions were lyophilized overnight to give the titledcompound as a yellow solid. ¹H NMR (DMSO-d₆): δ 8.96 (d, J=2.8 Hz, 1H),8.62 (m, 0.5H), 8.41 (m, 0.5H), 8.01-7.86 (m, 4H), 7.61-7.57 (m, 2H),7.35 (t, J=8.1 Hz, 1H), 7.26 (m, 2H), 7.17-7.12 (m, 2H), 7.02 (dd,J=8.2, 2.3 Hz, 1H), 6.96 (s, 1H), 6.82 (d, J=7.3 Hz, 1H), 6.46 (s,0.5H), 5.60 (d, J=12.1 Hz, 0.5H), 5.26 (s, 0.5H), 4.54-4.46 (m, 1.5H),4.50 (q, J=6.9 Hz, 2H), 3.89-3.76 (m, 3.5H), 3.43 (m, 0.5H), 3.25 (m,1H), 3.13 (m, 0.5H), 3.00 (m, 0.5H), 2.28 (s, 3H), 1.27 (t, J=7.0 Hz,3H). LC/MS 619.2 (M+1).

Example 4{[(2S)-1-{[1-(3-Ethoxyphenyl-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(3-quinolinyl)-2-piperazinyl]methoxy}aceticacid, trifluoroacetic acid salt

Step A:((2S)-1-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-quinolin-3-ylpiperazin-2-yl)methylacetate To 108 mg (0.118 mmol) oftris(dibenzylideneacetone)dipalladium(0), 279 mg (0.708 mmol) of2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, 1.92 g (5.90mmol) of cesium carbonate, and 1.82 g (3.93 mmol) of((2S)-1-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazin-2-yl)methylacetate (synthesized from Intermediate 1 and 1-benzyl3-methyl-(3S)-piperazine-1,3-dicarboxylate according to the proceduresoutlined for the preparation of Intermediate 4) was added 982 mg (4.72mmol) of 3-bromoquinoline. The flask was flushed with nitrogen and 20 mLof anhydrous 1,4-dioxane was added. The resulting reaction mixture washeated to 85° C. for 15 h, cooled to room temperature and diluted withwater (25 mL). After extraction with ethyl acetate (3×10 mL), thecombined organic layers were washed with brine (10 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo. The crude residuewas purified on a Biotage® purification apparatus (silica gel, 75% ethylacetate in hexanes then 100% ethyl acetate) to yield the title compoundas a yellow foam. LC/MS 590.2 (M+1).Step B:((2S)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-quinolin-3-ylpiperazin-2-yl)methanolTo a solution of 1.65 g (2.80 mmol) of((2S)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-quinolin-3-ylpiperazin-2-yl)methylacetate from Step A in 40 mL of tetrahydrofuran and 9 mL of methanol at0° C. was added 1.1 mL (0.56 mmol) of a 0.5 M solution of sodiummethoxide in methanol and the resulting mixture was stirred for 2 hours.The reaction was quenched with a saturated aqueous ammonium chloridesolution (10 mL) and the layers were separated. The aqueous layer wasextracted with ethyl acetate (3×10 mL) and the combined organic layerswere washed with brine (10 mL), dried over magnesium sulfate, filteredand concentrated in vacuo. The crude residue was purified on a Biotage®purification apparatus (silica gel, 30% acetone in hexanes) to yield thetitle compound as a yellow foam. LC/MS 548.1 (M+1).Step C:tert-butyl[((2S)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-quinolin-3-ylpiperazin-2-yl)methoxy]acetateTo a suspension of 4 mg (0.1 mmol) of a 60% dispersion of sodium hydridein mineral oil in 3 mL tetrahydrofuran at 0° C. under a nitrogenatmosphere was added 50 mg (0.09 mmol) of((2S)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-quinolin-3-ylpiperazin-2-yl)methanolfrom Step B. The resulting solution was allowed to warm to ambienttemperature and 0.018 mL (0.12 mmol) of tert-butyl bromoacetate wasadded. After stirring for 2 hours the reaction was quenched with water(5 mL) and extracted with a 3:1 chloroform/isopropyl alcohol mixture(3×5 mL). The organic layers were combined, dried over magnesiumsulfate, filtered, and evaporated in vacuo to yield a crude oil whichwas carried forward without purification. LC/MS 662.3 (M+1).Step D:{[(2S)-1-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(3-quinolinyl)-2-piperazinyl]methoxy}aceticacid, trifluoroacetic acid salt To a stirred solution of 40 mg (0.060mmol) oftert-butyl[((2S)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-quinolin-3-ylpiperazin-2-yl)methoxy]acetatefrom Step C in 1 mL dichloromethane was added 1.5 mL of trifluoroaceticacid. The resulting solution was stirred at ambient temperature for 2hours and concentrated in vacuo to yield a viscous crude oil, which waspurified by reverse phase HPLC(YMC Pro C-18 column, gradient elution, 10to 90% acetonitrile/water with 0.1% trifluoroacetic acid). The resultingpure fractions were lyophilized overnight to give the title compound asa yellow solid. ¹H NMR (CD₃OD): δ 9.11 (s, 1H), 8.38 (s, 1H), 8.03-8.19(m, 3H), 7.78-7.82 (m, 2H), 7.33-7.40 (m, 3H), 7.21-7.22 (m, 2H),7.04-7.06 (m, 1H), 6.93 (br s, 2H), 4.65-5.39 (m, 2H), 3.70-4.40 (m,8H), 3.16-3.60 (m, 3H), 2.36 (s, 3H), 1.31-1.35 (m, 3H). LC/MS 606.5(M+1).

Following essentially the procedures outlined for Examples 1-4, theExamples listed in Tables 1 and 2 were prepared.

TABLE 1

Example *Enantiomer R⁴ R⁶ Y MS (M + 1) 5 R OCH₃ CH₃ CH 547.3 6 S OCH₃CH₃ CH 547.3 7 R OCH₃ CH₃ N 548.3 8 S OCH₃ CH₃ N 548.3 9 S OCH₂CH₃ CH₃ N562.3 10 R OCH₂CH₃ F N 566.3 11 S OCH₂CH₃ F N 566.3

TABLE 2

Example *Enantiomer R⁹ Ar MS (M + 1) 12 R CONHCH₃ 4-CH₃Phenyl 575.2 13 SCONHCH₃ 4-CH₃Phenyl 575.3 14 R CONHCH₂CH₃ 4-CH₃Phenyl 589.2 15 RCON(CH₂CH₃)₂ 4-CH₃Phenyl 617.3 16 S CON(CH₂CH₃)₂ 4-CH₃Phenyl 617.3 17 RCONHCH(CH₃)₂ 4-CH₃Phenyl 603.5 18 S CONHCH(CH₃)₂ 4-CH₃Phenyl 603.5 19 RCONHC(CH)₃ 4-CH₃Phenyl 617.3 20 S CONHC(CH)₃ 4-CH₃Phenyl 617.3 21 RCONH(CH₂)₂CH₃ 4-CH₃Phenyl 603.3 22 S CONH(CH₂)₂CH₃ 4-CH₃Phenyl 603.3 23R CONH(CH₂)₃CH₃ 4-CH₃Phenyl 617.4 24 S CONH(CH₂)₃CH₃ 4-CH₃Phenyl 617.425 S

4-CH₃Phenyl 629.2 26 S

4-CH₃Phenyl 615.3 27 S

4-CH₃Phenyl 631.3 28 S CON(CH₃)₂ 4-CH₃Phenyl 589.3 29 S CONH(CH₂)₄CH₃4-CH₃Phenyl 631.3 30 S CONH(CH₂)₅CH₃ 4-CH₃Phenyl 645.2 31 S

4-CH₃Phenyl 630.3 32 S

4-CH₃Phenyl 601.2 33 R CH₂CO₂H 4-CH₃Phenyl 576.2 34 S CH₂CO₂H4-CH₃Phenyl 576.2 35 R CH₂OC(O)CH₃ 4-CH₃Phenyl 590.2 36 S CH₂OC(O)CH₃4-CH₃Phenyl 590.2 37 R CH₂OCH₂CO₂H 4-CH₃Phenyl 606.2 38 S CH₂NHCOCH₃4-CH₃Phenyl 589.6 39 R CH₂NHCOCH₃ 4-CH₃Phenyl 589.2 40 S CH₂NHCOCH(CH₃)₂4-CH₃Phenyl 616.9 41 S

4-CH₃Phenyl 615.4 42 S

4-CH₃Phenyl 643.3 43 S CH₂NHCOPhenyl 4-CH₃Phenyl 651.6 44 RCH₂NHCONHCH(CH₃)₂ 4-CH₃Phenyl 632.0 45 S CH₂NHCONHCH(CH₃)₂ 4-CH₃Phenyl632.0 46 S CH₂NHCONHCH₃ 4-CH₃Phenyl 604.2 47 R CH₂NHSO₂CH₃ 4-CH₃Phenyl625.1 48 S CH₂NHSO₂CH₃ 4-CH₃Phenyl 625.2 49 R

4-CH₃Phenyl 651.5 50 S CH₂NHCH₂CO₂H 4-CH₃Phenyl 605.2 51 R CH₂NHCH₂CO₂H4-CH₂Phenyl 605.2 52 S CO₂H 2,4- 584.1 difluorophenyl

Example 533-{(3S)-4-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoicacid, trifluoroacetic acid salt

Step A: Methyl3-{(3S)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoate,trifluoroacetic acid salt To a solution of 72 mg (0.22 mmol) ofIntermediate 1 and 105 mg (0.223 mmol) of Intermediate 6 in 3 mLN,N-dimethylformamide was added 48 mg (0.25 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarboiimide hydrochloride, 33 mg (0.25mmol) of 1-hydroxybenzotriazole, and 0.097 mL (0.56 mmol)N,N-diisopropylethylamine. The solution was allowed to stir at roomtemperature overnight. The reaction was quenched with 2 mL 0.01%trifluoroacetic acid in water, and the reaction mixture was purifieddirectly by reverse phase HPLC (TMC Pro-Pac C18; 30-100% 0.01%trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid in watergradient). The pure fractions were concentrated in vacuo to yield ayellow oil. LC/MS 660.1 (M+1).Step B:3-{(3S)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoicacid, trifluoroacetic acid salt To a solution of 150 mg (0.19 mmol) ofthe product of Step A in 6 mL of tetrahydrofuran was added 1.0 mLmethanol and 1.0 mL (1.0 mmol) of 1N lithium hydroxide solution. Whenthe reaction was complete by LC-MS (2 h) the solution was partitionedbetween 1N hydrochloric acid (5 mL) and ethyl acetate (100 mL). Theorganic layer was separated, dried over magnesium sulfate, filtered andconcentrated in vacuo to afford a yellow oil. The oil was taken up inN,N-dimethylformamide (2 mL), diluted with 0.01% trifluoroacetic acid inwater (0.5 mL), and purified by reverse phase HPLC (TMC Pro-Pac C18;30-100% 0.01% trifluoroacetic acid in acetonitrile/0.01% trifluoroaceticacid in water gradient). The pure fractions were lyophilized overnightto give the title compound as a pale yellow solid. ¹H NMR (DMSO-d₆): δ8.63 (d, J=8.4 Hz, 1H), 8.08-7.93 (m, 3H), 7.79 (d, J=8.2 Hz, 1H), 7.45(t, J=7.2 Hz, 1H), 7.38-7.34 (m, 3H), 7.27 (br, 2H), 7.17-7.11 (m, 2H),7.02 (d, J=8.3 Hz, 1H), 6.96 (br, 1H), 6.82 (br, 1H), 6.15 (s, 0.5H),5.48 (br, 0.5H), 5.05 (s, 0.5H), 4.49 (m, 0.5H), 4.39 (m, 1H), 4.01 (q,J=6.6 Hz, 2H), 3.94-3.84 (br, 1.5H), 3.75 (br, 1H), 3.46 (m, 0.5H), 3.13(m, 1H), 3.03 (m, 0.5H), 2.90 (m, 0.5H), 2.29 (s, 3H), 1.28 (t, J=6.8Hz, 3H), 1.11-1.01 (br, 6H). LC/MS 646.1 (M+1).

Example 543-((3R)-4-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]-carbonyl}-3-{[2-(methylamino)-2-oxoethoxy]methyl}-1-piperazinyl)-1-naphthoicacid, trifluoroacetic acid salt

Step A: Methyl3-[(3R)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-(hydroxymethyl)piperazin-1-yl]-1-naphthoateTo 62 mg (0.070 mmol) of tris(dibenzylideneacetone)-dipalladium(0), 161mg (0.410 mmol) of2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, 824 mg (2.53mmol) of cesium carbonate and 780 mg (1.70 mmol) of Inter-mediate 4 wasadded 493 mg (1.86 mmol) of Intermediate 5. The flask was flushed withnitrogen and 10 mL of anhydrous 1,4-dioxane was added. The resultingreaction mixture was heated to 85° C. for 15 h, cooled to roomtemperature and diluted with a saturated aqueous ammonium chloridesolution (10 mL). After extraction with ethyl acetate (2×10 mL), thecombined organic layers were washed with brine (5 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo. The resultingcrude residue was purified on a Biotage® purification apparatus (silicagel, 60% ethyl acetate in hexanes) to yield the title compound as acolorless solid. LC/MS 605.5 (M+1).Step B: Methyl3-((3R)-3-[(2-tert-butoxy-2-oxoethoxy)methyl]-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazin-1-yl)-1-naphthoateTo a suspension of 4.0 mg (0.10 mmol) of a 60% dispersion of sodiumhydride in mineral oil in 2 ml anhydrous tetrahydrofuran at ambienttemperature under a nitrogen atmosphere was added 50 mg (0.08 mmol) ofmethyl3-[(3R)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-(hydroxymethyl)-piperazin-1-yl]-1-naphthoatefrom Step A. After 15 min of stirring, 0.020 mL (0.010 mmol) oftert-butyl bromoacetate was added, and the reaction mixture was stirredan additional 3 h. Next, the reaction was quenched with a saturatedaqueous ammonium chloride solution (5 mL) and diluted with ethyl acetate(15 mL). The layers were separated and the organic layer was washed withbrine (15 mL), dried over magnesium sulfate, filtered and concentratedin vacuo to yield the title compound as a colorless gum, which was usedwithout further purification. LC/MS 719.3 (M+1).Step C:({(2R)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-[4-(methoxycarbonyl)-2-naphthyl]piperazin-2-yl}methoxy)aceticacid To a stirred solution of 16 mg (0.020 mmol) of methyl3-((3R)-3-[(2-tert-butoxy-2-oxoethoxy)methyl]-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazin-1-yl)-1-naphthoatefrom Step B in 1 mL of dichloromethane at ambient temperature was added1.5 mL of trifluoroacetic acid. The resulting solution was stirred atambient temperature for 2 h and concentrated in vacuo. The residue wasdiluted with a saturated aqueous sodium bicarbonate solution (5 mL) andextracted with dichloromethane (10 mL). The organic layer was washedwith brine (2 mL), dried over magnesium sulfate, filtered andconcentrated in vacuo to yield the title compound as a colorless gum,which was used without further purification. LC/MS 663.2 (M+1).Step D: Methyl3-((3R)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-{[2-(methylamino)-2-oxoethoxy]methyl}piperazin-1-yl)-1-naphthoateTo a solution of 15 mg (0.023 mmol) of({(2R)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-[4-(methoxy-carbonyl)-2-naphthyl]piperazin-2-yl}methoxy)aceticacid from Step C in 1 mL of anhydrous dichloro-methane at 0° C. wasadded 0.0040 mL (0.050 mmol) of 1-methylimidazole followed by 0.002 mL(0.025 mmol) of methanesulfonyl chloride. The resulting mixture wasstirred with gradual warming to ambient temperature over 10 min. Afterre-cooling the reaction mixture to 0° C., 0.012 mL (0.025 mmol) of a 2Msolution of methylamine in methanol was added and the reaction mixturewas allowed to warm to ambient temperature over 1 h. The reaction wasquenched with a saturated aqueous ammonium chloride solution (2 mL) andthe layers were separated. The aqueous layer was extracted withdichloromethane (4 mL) and the combined organic layers were washed withbrine (2 mL), dried over magnesium sulfate, filtered and concentrated invacuo to yield the title compound as a colorless solid, which was usedwithout further purification. LC/MS 676.1 (M+1).Step E:3-((3R)-4-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-{[2-(methylamino)-2-oxoethoxy]methyl}-1-piperazinyl)-1-naphthoicacid, trifluoroacetic acid salt To 10 mg (0.015 mmol) of methyl3-((3R)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-{[2-(methylamino)-2-oxoethoxy]methyl}piperazin-1-yl)-1-naphthoatefrom Step D in 2 mL of tetrahydrofuran, 0.7 mL of methanol, and 0.7 mLof water was added 3.0 mg (0.075 mmol) of lithium hydroxide monohydrate.The resulting solution was stirred at ambient temperature for 2 h,quenched with 0.10 mL (0.10 mmol) of a 1M aqueous hydrochloric acidsolution, concentrated in vacuo and purified directly by reverse phaseHPLC (TMC Pro-Pac C18; 10-100% 0.01% trifluoroacetic acid inacetonitrile/0.01% trifluoroacetic acid in water gradient). Theresulting pure fractions were lyophilized overnight to give the titlecompound as a white solid. LC/MS 662.2 (M+1).

Example 553-((3R)-3-[(Carboxymethoxy)methyl]-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid, trifluoroacetic acid salt

Step A: To 15 mg (0.023 mmol) of({(2R)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-[4-(methoxycarbonyl)-2-naphthyl]piperazin-2-yl}methoxy)aceticacid in 1 mL of tetrahydrofuran and 0.3 mL of methanol was added 0.3 mLof a 1M lithium hydroxide solution. The resulting solution was stirredat ambient temperature for 2 h then quenched with 1 mL of a 1M aqueoushydrochloric acid solution. The aqueous layer was extracted with a 3:1chloroform/isopropyl alcohol mixture (3×5 mL) and the combined organiclayers were dried over magnesium sulfate, filtered, and evaporated invacuo to yield a viscous crude oil, which was purified by reverse phaseHPLC(YMC Pro C-18 column, gradient elution, 10 to 90% acetonitrile/waterwith 0.1% trifluoroacetic acid). The resulting pure fractions werelyophilized overnight to give the title compound as a white solid. ¹HNMR (CD₃OD): δ 8.70-8.72 (m, 1H), 8.30-8.50 (m, 1H), 8.03 (s, 1H),7.79-7.80 (m, 1H), 7.37-7.46 (m, 5H), 7.27-7.28 (m, 2H), 6.97-7.09 (m,4H), 4.66-5.03 (m, 2H), 3.91-4.18 (m, 8H), 2.96-3.60 (m, 3H), 2.38 (s,3H), 1.29-1.35 (m, 3H). LC/MS 648.9 (M+1).

Example 563-((3R)-3-[(Acetylamino)methyl]-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid trifluoroacetic acid salt

Step A:[(2S)-1-{[1-(3-Ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(4-{[(triisopropylsilyl)oxy]methyl}-2-naphthyl)piperazin-2-yl]methylacetate To 37 mg (0.041 mmol) oftris(dibenzylideneacetone)dipalladium(0), 97 mg (0.25 mmol) of2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, 666 mg (2.05mmol) of cesium carbonate and 655 mg (1.36 mmol) of((2S)-1-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazin-2-yl)methylacetate (synthesized from Intermediate 2 and 1-benzyl3-methyl-(3S)-piperazine-1,3-dicarboxylate according to the proceduresoutlined for the preparation of Intermediate 4) was added 644 mg (1.64mmol) of Intermediate 7. The flask was flushed with nitrogen and 10 mLof anhydrous 1,4-dioxane was added. The resulting reaction mixture washeated to 85° C. for 15 h, cooled to room temperature and diluted withwater (5 mL). After extraction with ethyl acetate (3×15 mL), thecombined organic layers were dried over magnesium sulfate, filtered andconcentrated in vacuo. The crude residue was purified on a Biotage®purification apparatus (silica gel, 20 to 35% ethyl acetate in hexanesgradient) to yield the title compound as a yellow solid. LC/MS 793.1(M+1).Step B:{(2S)-1-{[1-(3-Ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-[4-(hydroxymethyl)-2-naphthyl]piperazin-2-yl}methylacetate To a solution of 950 mg (1.20 mmol) of[(2S)-1-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(4-{[(triisopropylsilyl)oxy]methyl}-2-naphthyl)piperazin-2-yl]methylacetate from Step A in 10 mL of tetrahydrofuran was added 1.3 mL (1.3mmol) of a 1M solution of tetrabutylammonium fluoride intetrahydrofuran. After stirring for 1 h the reaction was diluted with asaturated aqueous sodium bicarbonate solution (15 mL), the layersseparated, and the aqueous phase extracted with ethyl acetate (2×15 mL).The combined organic layers were washed with brine (5 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo. The crude residuewas purified on a Biotage® purification apparatus (silica gel, 90% ethylacetate in hexanes) to yield the title compound as a white foam. LC/MS636.9 (M+1).Step C:[(2S)-1-{[1-(3-Ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(4-formyl-2-naphthyl)piperazin-2-yl]methylacetate To a solution of 763 mg (1.20 mmol) of{(2S)-1-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-[4-(hydroxymethyl)-2-naphthyl]piperazin-2-yl}methylacetate from Step B in 15 mL of anhydrous dichloromethane under anatmosphere of nitrogen was added 0.15 mL (1.8 mmol) of pyridine, then534 mg (1.26 mmol) of Dess-Martin periodinane. The resulting solutionwas stirred at ambient temperature for 3 h, then quenched with asaturated aqueous sodium bicarbonate solution (5 mL). The layers wereseparated and the aqueous phase extracted with dichloromethane (2×10mL). The combined organic layers were washed with brine (25 mL), driedover magnesium sulfate, filtered and evaporated in vacuo. The cruderesidue was purified on a Biotage® purification apparatus (silica gel,40% ethyl acetate in hexanes) to yield the title compound as a yellowgum. LC/MS 634.9 (M+1).Step D: Methyl3-((3S)-3-[(acetyloxy)methyl]-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazin-1-yl)-1-naphthoateTo a solution of 650 mg (1.02 mmol) of[(2S)-1-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(4-formyl-2-naphthyl)piperazin-2-yl]methylacetate from Step C in 6 mL of 2-methyl-2-propanol was added 0.55 mL(5.1 mmol) of 2-methyl-2-butene followed by dropwise addition of asolution of 184 mg (1.54 mmol) of sodium dihydrogen phosphate and 174 mg(1.54 mmol) of sodium chlorite in 6 mL of water. The resulting mixturewas stirred at ambient temperature for 18 h then evaporated in vacuo toremove all volatiles. The residue was diluted with water (5 mL) and anaqueous 1 N hydrochloric acid solution was then added dropwise to thestirred mixture until a pH of 5 was achieved. The aqueous phase was thenextracted with ethyl acetate (3×10 mL) and the combined organic layerswere washed with brine (5 mL), dried over magnesium sulfate, filteredand evaporated in vacuo. The residue was then dissolved in 3 mL ofdiethyl ether and 3 mL of methanol, and the resulting solution cooled to0° C. To this was added 0.68 mL (1.4 mmol) of a 2M trimethylsilyl(diazomethane) solution in hexanes, and the mixture was stirred for 30min. The reaction was quenched with 0.25 mL (4.4 mmol) of glacial aceticacid and then evaporated in vacuo. The crude residue was purified bypreparative thin layer chromatography (silica gel, 50% ethyl acetate inhexanes) to yield the title compound as a yellow solid. LC/MS 665.3(M+1).Step E: Methyl3-[(3S)-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-(hydroxymethyl)piperazin-1-yl]-1-naphthoateTo a solution of 292 mg (0.439 mmol) of methyl3-((3S)-3-[(acetyloxy)methyl]-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazin-1-yl)-1-naphthoatefrom Step D in 8 mL of tetrahydrofuran and 2 mL of methanol at 0° C. wasadded 0.18 mL (0.088 mmol) of a 0.5 M solution of sodium methoxide inmethanol and the resulting mixture was stirred for 2 h. The reaction wasquenched with a saturated aqueous ammonium chloride solution (5 mL) andthe layers were separated. The aqueous layer was extracted with ethylacetate (3×5 mL) and the combined organic layers were washed with brine(5 mL), dried over magnesium sulfate, filtered and concentrated in vacuoto afford the title compound as a white solid, which was used withoutfurther purification. LC/MS 623.0 (M+1).Step F: Methyl3-((3S)-3-(azidomethyl)-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazin-1-yl)-1-naphthoateTo 200 mg (0.321 mmol) of methyl3-[(3S)-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-(hydroxymethyl)piperazin-1-yl]-1-naphthoatefrom Step E in 5 mL of anhydrous dichloromethane at 0° C. was added0.066 mL (0.38 mmol) of N,N-diisopropylethylamine and 0.027 mL (0.35mmol) of methanesulfonyl chloride. The reaction was allowed to warm toambient temperature over 1 h, then concentrated in vacuo to dryness. Theresidue was dissolved in 2 mL of anhydrous N,N-dimethylformamide and 104mg (1.60 mmol) of sodium azide was added to the solution. The resultingreaction mixture was stirred for 2 h, quenched with water (10 mL) andextracted with ethyl acetate (2×10 mL). The organic layer was washedwith brine (5 mL), dried over magnesium sulfate, filtered andconcentrated in vacuo to afford the title compound as a yellow oil,which was used without further purification. LC/MS 648.1 (M+1).Step G: Methyl3-((3R)-3-(aminomethyl)-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazin-1-yl)-1-naphthoateTo 16 mg (0.011 mmol) of 20% palladium hydroxide on carbon was added asolution of 165 mg (0.255 mmol) of methyl3-((3S)-3-(azidomethyl)-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4yl]carbonyl}piperazin-1-yl)-1-naphthoatefrom Step F in 5 mL of anhydrous methanol. The resulting suspension wasagitated under an atmosphere of hydrogen at 30 psi for 2 h then filteredthrough a plug of Celite®. The plug was washed with methanol (15 mL),and the combined filtrates were concentrated in vacuo to afford thetitle compound as a colorless foam, which was used without furtherpurification. LC/MS 622.1 (M+1).Step H: Methyl3-((3R)-3-[(acetylamino)methyl]-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazin-1-yl)-1-naphthoateTo a stirred solution of 39 mg (0.065 mmol) of methyl3-((3R)-3-(aminomethyl)-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazin-1-yl)-1-naphthoatefrom Step G in 3 mL of anhydrous dichloromethane at 0° C. was added0.017 mL (0.10 mmol) of N,N-diisopropylethylamine followed by 0.007 mL(0.1 mmol) of acetyl chloride. The resulting solution was allowed towarm to ambient temperature over 1 h and concentrated in vacuo to affordthe title compound as a yellow gum, which was used without furtherpurification. LC/MS 664.1 (M+1).Step I:3-((3R)-3-[(Acetylamino)methyl]-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazin-1-yl)-1-naphthoicacid, trifluoroacetic acid salt To a stirred solution of 43 mg (0.065mmol) of methyl3-((3R)-3-[(acetylamino)methyl]-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazin-1-yl)-1-naphthoatefrom Step H in 2 mL tetrahydrofuran was added 43 mg (0.33 mmol) ofpotassium trimethylsilanolate. The resulting solution was stirred atambient temperature for 15 h, then quenched with 0.5 mL (0.5 mmol) of a1M aqueous hydrochloric acid solution, concentrated in vacuo andpurified directly by reverse phase HPLC (TMC Pro-Pac C18; 10-100% 0.01%trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid in watergradient). The resulting pure fractions were lyophilized overnight togive the titled compound as a white solid. ¹H NMR (CD₃OD): δ 8.71 (d,J=8.5 Hz, 1H), 8.19 (br s, 1H), 8.05 (s, 1H), 7.80 (d, J=8.1 Hz, 1H),7.46-7.37 (m, 4H), 7.33-7.30 (m, 1H), 7.12 (d, J=7.8 Hz, 1H), 6.98 (d,J=10.1 Hz, 2H), 6.89-6.85 (m, 2H), 5.29-4.62 (m, 2H), 3.98-3.65 (m, 5H),3.65-2.89 (m, 4H), 2.38 (s, 3H), 1.93-1.84 (m, 3H), 1.34-1.31 (m, 3H).LC/MS 650.2 (M+1).

Example 573-{(3S)-4-{[1-(3-Ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoicacid, trifluoroacetic acid salt

Step A: Methyl3-{(3S)-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoate,trifluoroacetic acid salt To a solution of 15 mg (0.044 mmol) ofIntermediate 2 and 20 mg (0.043 mmol) of Intermediate 6 in 1 mLN,N-dimethylformamide was added 9 mg (0.05 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarboiimide hydrochloride, 6 mg (0.05mmol) of 1-hydroxybenzotriazole, and 0.026 mL (0.15 mmol)N,N-diisopropylethylamine. The solution was allowed to stir at roomtemperature overnight. The reaction was quenched with 1 mL of 0.01%trifluoroacetic acid in water, and the reaction mixture was purifieddirectly by reverse phase HPLC (TMC Pro-Pac C18; 30-100% 0.01%trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid in watergradient). The pure fractions were concentrated in vacuo to yield ayellow oil. LC/MS 678.3 (M+1).Step B:3-{(3S)-4-{[1-(3-Ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoicacid, trifluoroacetic acid salt To a solution of 15 mg (0.020 mmol) ofthe product of Step A in 3 mL of tetrahydrofuran was added 1.0 mLmethanol and 1.0 mL (1.0 mmol) of 1N lithium hydroxide solution. Whenthe reaction was complete by LC-MS (2 h) the solution was partitionedbetween 1N hydrochloric acid (5 mL) and ethyl acetate (50 mL). Theorganic layer was separated, dried over magnesium sulfate, filtered andconcentrated in vacuo to afford a yellow oil. This material was taken upin N,N-dimethylformamide (2 mL), diluted with 0.01% trifluoroacetic acidin water (0.5 mL), and purified by reverse phase HPLC (TMC Pro-Pac C18;30-100% 0.01% trifluoroacetic acid in acetonitrile/0.01% trifluoroaceticacid in water gradient). The pure fractions were lyophilized overnightto give the title compound as a pale yellow solid. ¹H NMR (DMSO-d₆): δ8.62 (d, J=8.7 Hz, 1H), 8.11 (s, 0.5H), 8.07 (s, 0.5H), 8.01 (d, J=7.1Hz, 0.5H), 7.95 (d, J=7.4 Hz, 0.5H), 7.92 (s, 1H), 7.78 (d, J=8.0 Hz,1H), 7.48-7.42 (m, 2H), 7.39-7.34 (m, 2H), 7.28 (t, J=7.8 Hz, 1H), 7.10(br, 1H), 7.06-6.98 (m, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.86 (d, J=12.5 Hz,1H), 6.74 (m, 1H), 6.09 (s, 0.5H), 5.44 (d, J=12.6 Hz, 0.5H), 5.05 (s,0.5H), 4.47 (d, J=12.4 Hz, 0.5H), 4.37 (d, J=12.6 Hz, 1H), 3.96 (q,J=6.6 Hz, 2H), 3.92-3.82 (br, 1.5H) 3.75 (br, 1H), 3.44 (br, 0.5H), 3.13(br, 1H), 3.01 (br, 0.5H), 2.99 (br, 0.5H), 2.33 (s, 3H), 1.25 (t, J=6.7Hz, 3H), 1.12-0.98 (br, 6H). LC/MS 664.2 (M+1).

Following essentially the procedures outlined in the Examples above, theExamples listed in Table 3 were prepared.

TABLE 3

acid Example R⁵ *Enantiomer R⁹ position MS (M + 1) 58 H racemate CO₂H3-acid 605.2 59 H R CO₂H 4-acid 605.3 60 H S CO₂H 4-acid 605.3 61 H RCONHCH(CH₃)₂ 4-acid 646.4 62 H R CH₂CONHCH(CH₃)₂ 4-acid 660.3 63 H SCH₂CONHCH(CH₃)₂ 4-acid 660.3 64 H S CH₂OCH₂CONHCH(CH₃)₂ 4-acid 690.3 65H R CH₂NHSO₂CH₃ 4-acid 668.2 66 H S CH₂NHCONHCH₃ 4-acid 647.3 67 H SCH₂NHCOCH₃ 4-acid 632.2 68 F S CH₂OCH₂CO₂H 4-acid 666.8 69 F SCH₂NHSO₂CH₃ 4-acid 686.1 70 F S CH₂NHCONHCH₃ 4-acid 665.0

Example 71(2S)-4-(4-Carboxy-2-naphthyl)-1-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-2-piperazinecarboxylicacid, trifluoroacetic acid salt

Step A: 1-tert-butyl 2-methyl(2S)-4-[4-(methoxycarbonyl)-2-naphthyl]piperazine-1,2-dicarboxylate To150 mg (0.614 mmol) of 1-tert-butyl 2-methylpiperazine-1,2-dicarboxylate and 195 mg (0.737 mmol) of Intermediate 5was added 6 mL anhydrous 1,4-dioxane. The system was purged for 5 minand then flushed with nitrogen. Next, 299 mg (0.921 mmol) of cesiumcarbonate was added to the flask, and the system was again purged for 5min, and then flushed with nitrogen. Next, 29 mg (0.074 mmol) of2-dicyclohexylphosphino-2′(N,N-dimethylamino)biphenyl, and 7 mg (0.01mmol) of bis(dibenzylideneacetone)palladium were added, and the systemwas again purged with nitrogen. Finally the reaction mixture was heatedat 85° C. under nitrogen for 24 h. After cooling to room temperature,the solution was filtered through Celite® and concentrated in vacuo toyield an orange oil, which was purified using a Biotage Horizon® system(10%-20% ethyl acetate in hexanes gradient) to give the title compoundas a racemic mixture. Chiral HPLC separation (Chiralcel AD, 30%2-propanol/heptane) afforded the R enantiomer (first eluting) and the Senantiomer (second eluting), each in ≧99% ee. LC/MS 429.2 (M+1).Step B: Methyl(2S)-4-[4-(methoxycarbonyl)-2-naphthyl]piperazine-1,2-dicarboxylate To75 mg (0.18 mmol) of the S enantiomer from Step A was added 5 mLdichloromethane and 0.5 mL trifluoroacetic acid. When the reaction wascomplete by LC-MS (1 h), the solution was concentrated in vacuo. Thereddish oil was next triturated with ethyl ether (3 mL), and filtered togive the title compound as a beige solid. LC/MS 329.2 (M+1).Step C: Methyl(2S)-4-(4-carboxy-2-naphthyl)-1-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-2-piperazinecarboxylate,trifluoroacetic acid salt To a solution of 49 mg (0.143 mmol) ofintermediate 8 and 63 mg (0.143 mmol) of the compound from Step B in 1.5mL N,N-dimethylformamide was added 31 mg (0.157 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarboiimide hydrochloride, 21 mg(0.157 mmol) of 1-hydroxybenzotriazole, and 0.062 mL (0.36 mmol)N,N-diisopropylethylamine. The solution was allowed to stir at roomtemperature overnight. The reaction was quenched with 2 mL 0.01%trifluoroacetic acid in water, and the reaction mixture was purifieddirectly by reverse phase HPLC (TMC Pro-Pac C18; 30-100% 0.01%trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid in watergradient). The pure fractions were concentrated in vacuo to yield ayellow oil. LC/MS 660.2 (M+1).Step D:(2S)-4-(4-Carboxy-2-naphthyl)-1-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-2-piperazinecarboxylicacid, trifluoroacetic acid salt To a solution of 95 mg (0.123 mmol) ofthe product of Step A in 6 mL of tetrahydrofuran was added 3.0 mLmethanol and 3.0 mL (1.0 mmol) of 1N lithium hydroxide solution. Whenthe reaction was complete by LC-MS (2 h), the solution was partitionedbetween 1N hydrochloric acid (5 mL) and ethyl acetate (100 mL). Theorganic layer was separated, dried over magnesium sulfate, filtered andconcentrated in vacuo to afford a yellow oil. This material was taken upin N,N-dimethylformamide (2 mL), diluted with 0.01% trifluoroacetic acidin water (0.5 mL), and purified by reverse phase HPLC (TMC Pro-Pac C18;30-100% 0.01% trifluoroacetic acid in acetonitrile/0.01% trifluoroaceticacid in water gradient). The pure fractions were lyophilized overnightto give the title compound as a pale yellow solid. ¹H NMR (DMSO-d₆): δ8.65 (d, J=8.7 Hz, 1H), 7.98-7.92 (m, 2H), 7.84 (d, J=8.3 Hz, 1H),7.51-7.37 (m, 5H), 7.25-7.18 (m, 2H), 7.00 (dd, J=5.9 Hz, 2.5 Hz, 1H),6.94 (d, J=8.7 Hz, 1H), 6.80 (m, 1H), 6.67 (s, 0.5H), 5.55 (d, J=12.4,0.5H), 5.29 (s, 0.5H), 4.47 (d, J=13.3 Hz, 0.5H), 4.34 (d, J=12.2 Hz,1H), 4.28 (m, 4H), 3.86 (d, J=11.2 Hz, 0.5H), 3.80 (d, J=11.2 Hz, 0.5H),3.69 (dt, J=13.5 Hz, 2.9 Hz, 0.5H), 3.28 (dt, J=13.3 Hz, 3.5 Hz, 0.5H)3.15 (dd, J=12.6 Hz, 3.9 Hz, 0.5H), 3.08 (dd, J=12.6 Hz, 3.9 Hz, 0.5H),2.96 (m, 0.5H), 2.86 (m, 0.5H). LC/MS 623.2 (M+1).

Following essentially the procedures outlined in the Examples above, theExamples listed in Table 4 were prepared.

TABLE 4

Example *Enantiomer R⁹ R⁶ Y R¹⁴ MS (M + 1) 72 R CO₂H CH₃ N — 576.6 73 SCO₂H CH₃ N — 576.6 74 S CONHCH₂CH₃ CH₃ N — 603.3 75 R CO₂H F N — 580.276 S CO₂H F N — 580.2 77 S CONHCH(CH₃)₂ CH₃ CR¹⁴ CO₂H 660.2

Example 783-[1-{[1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperidin-4-yl]propanoicacid, trifluoracetic acid salt

Step A: Benzyl4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-4-(2-naphthyl)piperidine-1-carboxylateTo a solution of 0.30 mL (2.0 mmol) of trimethyl phosphonoacetate in 5mL of anhydrous tetrahydrofuran at 0° C. was added 0.540 mL (1.34 mmol)of a 2.5 M solution of n-butyl lithium in hexanes. The resulting mixturewas stirred for 1 h, then a solution of 250 mg (0.670 mmol) ofIntermediate 10 in anhydrous tetrahydrofuran was added. The resultingmixture was stirred with gradual warming to ambient temperature over 3h, and then quenched with a saturated aqueous ammonium chloride solution(15 mL). The aqueous layer was extracted with diethyl ether (3×10 mL),and the combined organic layers were washed with water (2×5 mL), brine(5 mL), dried over magnesium sulfate, filtered and concentrated invacuo. The crude residue was purified by preparative thin layerchromatography (silica gel, 35% ethyl acetate in hexanes) to afford thetitle compound as a clear oil. LC/MS 452.1 (M+Na).Step B: Methyl 3-[4-(2-naphthyl)piperidin-4-yl]propanoate To 20 mg(0.028 mmol) of 20% palladium hydroxide on carbon was added a solutionof 180 mg (0.419 mmol) of benzyl4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-4-(2-naphthyl)piperidine-1-carboxylatefrom Step A in 15 mL of anhydrous methanol. The resulting suspension wasagitated under an atmosphere of hydrogen at 30 psi for 2 h then filteredthrough a plug of Celite®. The plug was washed with methanol (15 mL),and the combined filtrates were concentrated in vacuo to afford thetitle compound as a tan solid, which was used without furtherpurification. LC/MS 298.2 (M+1).Step C: Methyl3-[1-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4yl]carbonyl}-4-(2-naphthyl)piperidin-4-yl]propanoateTo a solution of 25 mg (0.074 mmol) of1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylicacid (prepared according to the procedures outlined for Intermediate 8)and 44 mg (0.015 mmol) of methyl3-[4-(2-naphthyl)piperidin-4-yl]propanoate from Step B in 2 mL ofanhydrous dichloromethane was added 0.052 mL (0.30 mmol)N,N-diisopropylethylamine, 21 mg (0.11 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarboiimide hydrochloride, and 15 mg(0.11 mmol) of 1-hydroxy-7-azabenzotriazole. The solution was allowed tostir at ambient temperature overnight. The reaction was quenched with asaturated aqueous ammonium chloride solution (5 mL) and the aqueouslayer was extracted with dichloromethane (3×5 mL). The combined organiclayers were dried over magnesium sulfate, filtered and concentrated invacuo. The resulting crude residue was purified by preparative thinlayer chromatography (silica gel, 85% ethyl acetate in hexanes) toafford the title compound as a white solid. LC/MS 616.2 (M+1).Step D:3-[1-{[1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperidin-4-yl]propanoicacid, trifluoracetic acid salt To a stirred solution of 45 mg (0.073mmol) of methyl3-[1-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperidin-4-yl]propanoatefrom Step C in 1 mL of tetrahydrofuran was added 28 mg (0.22 mmol) ofpotassium trimethylsilanolate. The resulting solution was stirred atambient temperature for 18 h, quenched with 0.5 mL (0.5 mmol) of a 1Maqueous hydrochloric acid solution and concentrated in vacuo. The cruderesidue was purified directly by reverse phase HPLC (TMC Pro-Pac C18;10-100% 0.01% trifluoroacetic acid in acetonitrile/0.01% trifluoroaceticacid in water gradient). The resulting pure fractions were lyophilizedovernight to give the titled compound as a white solid. ¹H NMR(DMSO-d₆): δ 7.92-7.88 (m, 5H), 7.60 (d, J=8.7 Hz, 1H), 7.51-7.46 (m,2H), 7.27 (d, J=8.0 Hz, 2H), 7.18 (d, J=8.0 Hz, 2H), 6.99 (d, J=2.5 Hz,1H), 6.92 (d, J=8.7 Hz, 1H), 6.78 (dd, J=8.5, 2.3 Hz, 1H), 4.50 (br s,1H), 4.27-4.26 (m, 4H), 4.02 (br s, 1H), 3.68 (br s, 1H), 3.22 (br s,1H), 2.35-2.33 (m, 2H), 2.30 (s, 3H), 1.96-1.93 (m, 2H), 1.85-1.82 (m,4H). LC/MS 602.4 (M+1).

Example 794-(4-Carboxy-2-naphthyl)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-piperidinecarboxylicacid, trifluoracetic acid salt

Step A: 1-tert-Butyl 4-methyl4-(4-{[(triisopropylsilyl)oxy]methyl}-2-naphthyl)piperidine-1,4-dicarboxylateTo a solution of 1.5 mL (7.6 mmol) of dicyclohexylamine in 15 mL ofanhydrous toluene at −78° C. under an atmosphere of nitrogen was added3.0 mL (7.6 mmol) of a 2.5 M solution of n-butyl lithium in hexanes. Theresulting mixture was stirred with gradual warming to ambienttemperature over 30 min then recooled to −78° C. A solution of 1.86 g(7.63 mmol) of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate in 5mL of anhydrous toluene was added and the resulting mixture was stirredwith gradual warming to ambient temperature over 30 min. Next, 145 mg(0.159 mmol) of tris(dibenzylideneacetone)-dipalladium(0), 0.970 mL(0.318 mmol) of a 10% solution of tri-tert-butylphosphine in hexanes anda solution of 2.50 g (6.35 mmol) of Intermediate 7 in 10 mL of anhydroustoluene were added in sequence and the resulting dark brown suspensionwas stirred overnight at ambient temperature under an atmosphere ofnitrogen. All volatiles were then removed in vacuo and the residuediluted with 100 mL of water and 50 mL of ethyl acetate. The layers wereseparated and the aqueous layer was extracted with ethyl acetate (2×50mL). The combined organic layers were washed with brine (5 mL), driedover magnesium sulfate, filtered and concentrated in vacuo. The cruderesidue was purified on a Biotage® purification apparatus (silica gel,10% ethyl acetate in hexanes) to yield the title compound as a yellowgum. LC/MS 578.2 (M+Na⁺).Step B: 1-tert-Butyl 4-methyl4-[4-(hydroxymethyl)-2-naphthyl]piperidine-1,4-dicarboxylate To asolution of 1.90 g (3.42 mmol) of the above 1-tert-butyl 4-methyl4-(4-{[(triisopropylsilyl)oxy]methyl}-2-naphthyl)piperidine-1,4-dicarboxylatein 30 mL of tetrahydrofuran was added 5.1 mL (5.1 mmol) of a 1.0 Msolution of tetrabutylammonium fluoride in tetrahydrofuran. Afterstirring for 30 min the reaction mixture was concentrated in vacuo andthe crude residue was purified on a Biotage® purification apparatus(silica gel, 40% ethyl acetate in hexanes) to yield the title compoundas a white solid. LC/MS 422.1 (M+Na⁺).Step C: 1-tert-Butyl 4-methyl4-(4-formyl-2-naphthyl)piperidine-1,4-dicarboxylate To a solution of1.40 g (3.50 mmol) of the above 1-tert-butyl 4-methyl4-[4-(hydroxymethyl)-2-naphthyl]piperidine-1,4-dicarboxylate in 25 mL ofanhydrous dichloromethane under an atmosphere of nitrogen was added 1.4mL (17 mmol) of pyridine followed by 1.78 g (4.21 mmol) of Dess-Martinperiodinane. The resulting solution was stirred at ambient temperaturefor 30 min then quenched with a saturated aqueous sodium bicarbonatesolution (10 mL). The layers were separated and the aqueous phaseextracted with dichloromethane (2×50 mL). The combined organic layerswere washed with brine (25 mL), dried over magnesium sulfate, filteredand evaporated in vacuo. The crude residue was purified on a Biotage®purification apparatus (silica gel, 7% ethyl acetate in hexanes) toyield the title compound as a white solid. LC/MS 420.2 (M+Na⁺).Step D:3-[1-(tert-Butoxycarbonyl)-4-(methoxycarbonyl)piperidin-4-yl]-1-naphthoicacid To a solution of 1.23 g (3.09 mmol) of the above 1-tert-butyl4-methyl 4-(4-formyl-2-naphthyl)piperidine-1,4-dicarboxylate in 23 mL of2-methyl-2-propanol was added 0.990 mL (9.28 mmol) of 2-methyl-2-butenefollowed by dropwise addition of a solution of 743 mg (6.19 mmol) ofsodium dihydrogen phosphate and 644 mg (7.12 mmol) of sodium chlorite in23 mL of water. The resulting mixture was stirred at ambient temperaturefor 3 h then evaporated in vacuo to remove all volatiles. The residuewas diluted with a saturated aqueous sodium carbonate solution (25 mL)and water (25 mL) and then extracted with diethyl ether (2×10 mL). Anaqueous 2 N hydrochloric acid solution was then added dropwise to theaqueous phase until a pH of 6 was achieved. The aqueous phase was thenextracted with diethyl ether (3×25 mL) and the combined organic layerswere washed with brine (15 mL), dried over magnesium sulfate, filteredand evaporated in vacuo to yield the title compound as a white solid.LC/MS 436.1 (M+Na⁺).Step E: 1-tert-Butyl 4-methyl4-{4-[(benzyloxy)carbonyl]-2-naphthyl}piperidine-1,4-dicarboxylate To asolution of 1.20 g (2.90 mmol) of the above3-[1-(tert-butoxycarbonyl)-4-(methoxycarbonyl)piperidin-4-yl]-1-naphthoicacid in 30 mL of anhydrous dichloromethane at 0° C. was added 0.580 mL(7.26 mmol) of 1-methylimidazole followed by 0.250 mL (3.19 mmol) ofmethanesulfonyl chloride and the resulting mixture was stirred withgradual warming to ambient temperature over 30 min. After re-cooling thereaction mixture to 0° C., 0.900 mL (8.71 mmol) of benzyl alcohol and 18mg (0.15 mmol) of 4-(dimethylamino)pyridine were added and the reactionmixture was allowed to warm to ambient temperature over 1 h. Thereaction was quenched with a saturated aqueous ammonium chloridesolution (20 mL) and the layers were separated. The aqueous layer wasextracted with dichloromethane (2×25 mL) and the combined organic layerswere washed with brine (15 mL), dried over magnesium sulfate, filteredand concentrated in vacuo. The crude residue was purified on a Biotage®purification apparatus (silica gel, 5 to 10% gradient of ethyl acetatein hexanes) to yield the title compound as a colorless gum. LC/MS 526.1(M+Na⁺).Step F: Methyl4-{4-[(benzyloxy)carbonyl]-2-naphthyl}piperidine-4-carboxylate To astirred solution of 1.24 g (2.46 mmol) of 1-tert-butyl 4-methyl4-{4-[(benzyloxy)carbonyl]-2-naphthyl}piperidine-1,4-dicarboxylate in 10mL of dichloromethane at ambient temperature was added 10 mL oftrifluoroacetic acid. The resulting solution was stirred at ambienttemperature for 2 h and concentrated in vacuo. The residue was dilutedwith a saturated aqueous sodium bicarbonate solution (25 mL) andextracted with dichloromethane (3×20 mL). The organic layer was washedwith brine (10 mL), dried over magnesium sulfate, filtered andconcentrated in vacuo to yield the title compound as a colorless gum,which was used without further purification. LC/MS 404.4 (M+1).Step G: Methyl4-{4-[(benzyloxy)carbonyl]-2-naphthyl}-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperidine-4-carboxylateTo a solution of 352 mg (1.09 mmol) of Intermediate 1 in 10 mL ofanhydrous dichloromethane at 0° C. was added 0.200 mL (2.48 mmol) of1-methylimidazole followed by 0.085 mL (1.09 mmol) of methanesulfonylchloride. The resulting mixture was stirred with gradual warming toambient temperature over 30 min then re-cooled to 0° C. A solution of400 mg (0.991 mmol) of the above methyl4-{4-[(benzyloxy)carbonyl]-2-naphthyl}piperidine-4-carboxylate in 7 mlof anhydrous dichloromethane and 6.0 mg (0.050 mmol) of4-(dimethylamino)-pyridine were then added and the reaction mixture wasallowed to warm to ambient temperature over 2 h. The reaction wasquenched with a saturated aqueous ammonium chloride solution (10 mL) andthe layers were separated. The aqueous layer was extracted withdichloromethane (3×10 mL) and the combined organic layers were driedover magnesium sulfate, filtered and concentrated in vacuo. The cruderesidue was purified on a Biotage® purification apparatus (silica gel,40% ethyl acetate in hexanes) to yield the title compound as a colorlessgum. LC/MS 708.2 (M+1).Step H:4-(4-Carboxy-2-naphthyl)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-piperidinecarboxylicacid, trifluoracetic acid salt To a stirred solution of 25 mg (0.035mmol) of the above methyl4-{4-[(benzyloxy)carbonyl]-2-naphthyl}-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperidine-4-carboxylatein 2 mL of tetrahydrofuran was added 14 mg (0.10 mmol) of potassiumtrimethylsilanolate. The resulting solution was stirred at ambienttemperature for 15 h, quenched with 0.200 mL of trifluoroacetic acid,concentrated in vacuo and purified directly by reverse phase HPLC (TMCPro-Pac C18; 10-100% 0.01% trifluoroacetic acid in acetonitrile/0.01%trifluoroacetic acid in water gradient). The resulting pure fractionswere lyophilized overnight to give the titled compound as a white solid.¹H NMR (DMSO-d₆): δ 313.05 (br s, 1H), 8.80 (d, J=8.0 Hz, 1H), 8.21 (s,2H), 8.05 (d, J=8.5 Hz, 1H), 7.96 (s, 1H), 7.64-7.67 (m, 2H), 7.34 (t,J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 7.02-6.98(m, 2H), 6.83 (d, J=8.0 Hz, 1H), 4.96 (br s, 1H), 4.36 (br s, 1H), 4.00(q, J=7.0 Hz, 2H), 3.61 (br s, 1H), 3.17 (br s, 1H), 2.62 (d, J=12.5 Hz,2H), 2.28 (s, 3H), 2.00 (br s, 2H), 1.26 (t, J=7.0 Hz, 3H). LC/MS 604.3(M+1).

Following essentially the procedures outlined in the Examples above, theExamples listed in Tables 5 and 6 were prepared.

TABLE 5

Example R⁵ R¹⁶ Y R¹⁴ MS (M + 1) 80 H CO₂H CR¹⁴ H 560.1 81 H OCH₂CO₂H N —591.1 82 H CO₂H N — 561.0 83 H CO₂H CR¹⁴ CONHCH₃ 617.3 84 H CO₂H CR¹⁴CON(CH₃)₂ 631.4 85 H CO₂H CR¹⁴ CONHCH(CH₃)₂ 645.4 86 H CONHCH₃ CR¹⁴ CO₂H617.2 87 H CON(CH₃)₂ CR¹⁴ CO₂H 631.3 88 H CO₂H CR¹⁴

643.5 89 H CO₂H CR¹⁴ CONHCH₂CH₃ 631.3 90 H CO₂H CR¹⁴ CONHPhenyl 679.4 91H CO₂H CR¹⁴ CON(CH₂CH₃)₂ 659.5 92 H CO₂H CR¹⁴ CONHCH₂CO₂H 661.3 93 HCO₂H CR¹⁴ CON(CH₃)CH₂CO₂H 675.3 94 H CO₂H CR¹⁴

657.0 95 H CO₂H CR¹⁴

673.5 96 F CO₂H CR¹⁴ CO₂H 622.0 97 F CO₂H CR¹⁴ CONHCH₂CO₂H 679.0 98 FCONHCH₂CO₂H CR¹⁴ CO₂H 679.0 99 F CO₂H CR¹⁴ CONH₂ 621.0 100 F CONH₂ CR¹⁴CO₂H 621.0

TABLE 6

Example R⁵ R¹⁶ Y R¹⁴ MS (M + 1) 101 H NHCOMe CR¹⁴ CO₂H 631.2 102 HNHCONHMe CR¹⁴ CO₂H 646.0 103 H CH₂CO₂H CR¹⁴ H 588.3 104 H trans- CR¹⁴ H600.3 CHCHCO₂H

Biological Assays A. Cholecystokinin-1 Receptor (CCK1R) andCholecystokinin-2 Receptor (CCK2R) Binding Assays

Cells were cultured to confluence and harvested by aspirating culturemedium and rinsed twice with 1×PBS without Mg⁺⁺ and Ca⁺⁺. 3 ml of CellDissociate Solution was added to each T-175 flask until all cellsdissociated and then an additional 15 ml 1×PBS without Mg⁺⁺ and Ca⁺⁺ wasadded to each flask. Dissociated cells were collected in a centrifugetube by centrifuging at 1000 rpm for 10 min. The cell pellet washomogenized at 4° C. using a Polytron (setting 40, 20 stokes) in about10 ml/T175 flask membrane preparation buffer (10 mM Tris pH 7.4, 0.01 mMPefabloc, 10 μM phosphoramidon and 40 μg/ml Bacitracin). Aftercentrifugation at 2200 rpm (1000×g) for 10 min at 4° C., the supernatantwas transferred to a clean centrifuge tube and spun at 18,000 rpm(38,742×g) for 15 min. at 4° C. Membranes were resuspended with theabove membrane preparation buffer (1000 μl per T-175 flask),homogenized, aliquoted, quickly frozen in liquid nitrogen and stored at−80° C. The specific binding of ¹²⁵I-Bolton Hunter-CCK-8S to CCK1R orCCK2R was measured by filtration binding assay in 96 well plate format.0.5 μg membrane/well in binding buffer (50 mM Tris pH 7.4, 5 mM MgCl₂,200 μg/ml Bacitracin and protease inhibitor cocktail) was mixed withagonists in 1% DMSO (final concentration) and 0.1 nM ¹²⁵I-BoltonHunter-CCK-8S was added. After incubation for 1-2 hrs at roomtemperature, membrane-bound ¹²⁵I-Bolton Hunter-CCK8S was separated fromthe free ¹²⁵I-Bolton Hunter-CCK8S by filtering through GF/C filterspresoaked in 0.2% BSA solution. The filters were washed with ice-coldwashing buffer (50 mM Tris pH 7.4, 10 mM MgCl₂, 2 mM EDTA and 0.04%Tween 20). The radioactivity was determined by adding 30 μl ofmicroscintillant/well after each plate was dried at room temperatureovernight or placed at 55° C. for 30 mins. A Packard Top Count was thenused to read each filter plate. The data in cpms was plotted vs. the logmolar concentration of receptor ligand (compound). The IC₅₀ was reportedas the inflection point of the resulting sigmoidal curve. The maximuminhibition observed at the highest compound concentration was reportedfor compounds which do not generate a curve.

B. Cell Culture of Cholecystokinin-1 Receptor (CCK1R) andCholecystokinin-2 Receptor (CCK2R) Cell Lines

Stable CHO cell lines expressing the human CCK1R and CCK2R cDNA andstable HEK293 cell lines expressing the human CCK2R cDNA were generatedusing standard cell biology techniques. One CCK1R clone identified asCHO_WT23 was used for both FLIPR and IP3 functional and binding assays.One CCK2R clone called CHO_B101 was used for FLIPR functional assays andanother CCK2R clone, CHO_hCCK2R, was used for IP3 functional assays.Both WT23 and B101 cells were routinely cultured in T175 flasks inIscoves Modified Dulbecco's Medium (Invitrogen #12440-046) supplementedwith 10% FBS (cat# SH30070.03, Hyclone, Logan, Utah), 1×HT Supplement(0.1 mM Sodium Hypoxanthine and 16 μM Thymidine), 100 units/mlPennicillin-G and 100 μg/ml Streptomycin, 2 mM L-Glutamine and 1 mg/mlGeneticin. hCCK2R/CHO/Flip-in cells were routinely cultured in T175flasks in F-12 Nutrient Mixture (Ham) supplemented with 10% FBS (cat#SH30070.03, Hyclone, Logan, Utah), 100 units/ml Pennicillin-G and 100μg/ml Streptomycin, 2 mM L-Glutamine and 150 μg/ml Hygromycin. OneHek293 hCCK2R clone identified as Hek293_hCCK2R#37 was used for bindingassays. Hek293_hCCK2R#37 cells were routinely cultured in T175 flasks inDulbecco's Modified Eagle Medium, with high glucose (Invitrogen Cat #11965-084) supplemented with 10% FBS (cat# SH30070.03, Hyclone, Logan,Utah), 25 mM of HEPES Buffer Solution (Invitrogen cat#15630-080), 500μg/ml Geneticin (Invitrogen cat# 10131-027) and 200 μg/ml Hygromycin.Cells were grown as attached monolayers in tissue culture flasks underappropriate media in an incubator at 37° C. with 5% CO₂. Cells werepassed 1:5 for CHO_WT23, B101 and CHO_hCCK2R cells and 1:3 for HEK293_hCCK2R#37 twice a week. Cell culture media, antibiotics, FetalBovine Serum were all from Invitogen Technologies Inc. unless otherwisespecified.

C. Cholecystokinin-1 Receptor (CCK1R) and Cholecystokinin-2 Receptor(CCK2R) Functional Assays 1) FLIPR (Flurometric Imaging Plate Reader,Molecular Devices, Sunnyvale, Calif.)

CHO_WT23 and B101 cells cultured as described above were detached withTrypsin-EDTA and 20 μl volume of cells were seeded in 384 well plate at62,500 cells/ml. The cells grew overnight at 37° C. with 5% CO₂ in ahumidified atmosphere. On the day of the assay, the cells were loadedwith 20 μl/well of No-wash assay buffer (HBSS, 0.1% BSA, 20 mM HEPES,2.5mM Probenecid and 1.6 mM TR40 Quenching Solution) containing 8 μMFluo-4 AM in the dark at room temperature for 1.5 hrs. Agonists weredissolved in DMSO and diluted into assay buffer. 13.3 μl/well of 4×concentration of agonist solution was added to cells while measuringfluorescence. The EC₅₀ for activation of the CCK1R or CCK2R receptor wasreported as the inflection point of the resulting sigmoidal curve.

2) Inositol Phosphate SPA Assay (IP3) to Measure IP3 Accumulation

This functional assay was performed in a 96-well format. On the firstday, 75 μl of CHO cells at 62,500/ml were plated on poly-D-lysineplates. On the afternoon of the next day, the plates were aspirated, andthe cells were washed with PBS w/o Mg⁺⁺, Ca⁺⁺. Next 150 μl of³H-inositol labeling media, Inositol-free DMEM media ICN #1642954supplemented with 10% FBS, 1× pen/strep/glutamine to which³H-myo-inositol (NEN #NET114A) was added, 1 mCi/ml, 25 Ci/mmol diluted1:150 in loading medium (final specific radioactivity of 1 μCi/150 μl).After 18 hours of labeling, 5 μl 300 mM LiCl was added to the wells,mixed, and incubated for 20 minutes at 37° C., then 1.5 μl DMSO of 200×compounds were added to wells and incubated for an additional 90 minutesat 37° C. Plates were aspirated, and then the reaction was terminatedand cells were lysed with the addition of 60 μl 10 mM formic acid for 60minutes at room temperature. 20 μl of lysate was transferred toclear-bottom Opti-plates which contained RNA binding YSi SPA-beads(Amershamn RPNQ0013) that were suspended in 10% glycerol at 1 mgbeads/70 μl of solution and dispensed at 70 μl per well. After mixing,the plates sit at room temperature for 2 hrs and were then counted usinga Wallac Microbeta reader. The EC₅₀ for activation of the CCK1F or CCK2Rreceptor was calculated from the titration curve of the compounds.

D. In Vivo Overnight Food Intake and Body Weight in C57 Lean Male Mice

Methods: Male C57 mice, approximately 8 weeks old (weighingapproximately 25 g) were individually housed and acclimated for severaldays prior to testing. Mice were orally dosed (PO; n=8) with eithervehicle controls (10% Tween-water) or CCK1R agonists (various doses). Aknown CB1 inverse agonist, AM251 (3 mg/kg) was used as the positivecontrol for inter- and intra-experimental control. CCK1R agonists weredosed (PO) approximately 60-120 minutes prior to the onset of the darkcycle. Overnight food intake (g) and body weight (g) (±SEM) werecollected and analyzed. All data were presented as mean±SEM (n=8).Statistical significance was calculated using Student's t-test todetermine whether compared the groups were statistically distinct.Differences were considered significant when p<0.05.

Compounds useful in the present invention decrease overnight food intakeby at least 10% and/or decrease body weight overnight by at least 1%relative to placebo.

E. Mouse Gallbladder Emptying Assay for CCK-1R Binding Specificity

Methods: Male CD-1 mice, approximately 7-8 weeks old (weighing 25 g)were housed (8 mice per cage), and fasted for 18 hours with ad libaccess to water. Mice were orally dosed (PO; n=8) with either vehiclecontrols (10% Tween-water) or CCK1R agonists (various doses) for 4 h.After 4 h, mice were deeply anesthetized with CO₂ inhalant; bloodsamples were drawn via cardiac puncture and stored at −20° C. (forfuture assays). Gall bladders were isolated, removed and weighed.Gallbladder weights were normalized to body weight (g/kg) and comparedto vehicle control group. The entire assay typically requiredapproximately 30-40 minutes for tissue collection. All data werepresented as mean±SEM (n=8) and Statistical significance was calculatedusing Student's t-test to determine whether compared the groups werestatistically distinct. Differences were considered significant whenp<0.05.

Representative compounds of the present invention were tested and foundto bind to the cholecystokinin-1 receptor. Representative compounds ofthe present invention were found to have IC₅₀ values less than or equalto 500 nM. Representative compounds of the present invention were alsotested in the functional assay and found to activate thecholecystokinin-1 receptor with EC₅₀ values less than or equal to 500nM.

Examples of Pharmaceutical Compositions

As a specific embodiment of an oral composition of a composition of thepresent invention, 5 mg of Example 1 is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size O hard gelatin capsule.

As another specific embodiment of an oral composition of a compound ofthe present invention, 2.5 mg of Example 1 is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size O hard gelatin capsule.

While the invention has been described and illustrated in reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferred dosesas set forth hereinabove may be applicable as a consequence ofvariations in the responsiveness of the subject or mammal being treatedobesity, diabetes, obesity-related disorders, or for other indicationsfor the compounds of the invention indicated above. Likewise, thespecific pharmacological responses observed may vary according to anddepending upon the particular active compound selected or whether thereare present pharmaceutical carriers, as well as the type of formulationand mode of administration employed, and such expected variations ordifferences in the results are contemplated in accordance with theobjects and embodiments of the present invention. It is intended,therefore, that the invention be limited only by the scope of the claimswhich follow and that such claims be interpreted as broadly as isreasonable.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein X is N or CR¹⁶;R¹, R², R³ and R⁴ are each independently selected from the groupconsisting of: (1) hydrogen, (2) halogen, (3) —OH, (4) —C₁₋₆alkyl, (5)—C₁₋₆alkoxy, (6) —SC₁₋₆-alkyl, (7) —S(O)C₁₋₆-alkyl, (8)—S(O)₂C₁₋₆-alkyl, (9) —NHC₁₋₆-alkyl, and (10) —N(C₁₋₆-alkyl)₂, whereinalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy, or R²and R³ or R³ and R⁴ together with the atoms to which they are attachedform a 4-8 membered ring containing 0-2 heteroatoms independentlyselected from oxygen, sulfur, and N—R¹⁵, and wherein the 4-8 memberedring is unsubstituted or substituted with a substituent selected fromOH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy; R⁵, R⁶ and R⁷ are eachindependently selected from the group consisting of: (1) hydrogen, (2)halogen, (3) —OH, (4) —C₁₋₆alkyl, and (5) —C₁₋₆alkoxy, wherein alkyl andalkoxy are unsubstituted or substituted with one to five substituentsindependently selected from halogen, —OH, C₁₋₆alkyl, and C₁₋₆alkoxy, orR⁵ and R⁶ or R⁶ and R⁷ together with the atoms to which they areattached form a 4-8 membered ring containing 0-2 heteroatomsindependently selected from oxygen, sulfur, and N—R¹⁵, and wherein the4-8 membered ring is unsubstituted or substituted with a substituentselected from OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy; R⁸ isindependently selected from the group consisting of: (1) hydrogen, (2)halogen, (3) —C₁₋₆alkyl, (4) —C₁₋₆alkoxy, and (5) —C₃₋₆cycloalkyl; R⁹and R¹⁶ are each independently selected from the group consisting of:(1) hydrogen, (2) -(CH₂)_(n)CF₃, (3) -(CH₂)_(n)OH, (4) -(CH₂)_(n)CN, (5)-C₁₋₆alkyl, (6) -C₁₋₆alkoxy, (7) -(CH₂)_(n)C₃₋₈cycloalkyl, (8)-(CH₂)_(n)NR¹¹R¹², (9) -a 5-10 membered aromatic monocyclic or bicyclicheterocyclic ring, (10) phenyl, (11) -C₂₋₆alkene-CO₂R¹², (12)-(CH₂)_(n)C(O)R¹², (13) -(CH₂)_(n)CO₂R¹², (14) -(CH₂)_(n)OC(O)R¹², (15)-(CH₂)_(n)O(CH₂)_(n)CO₂R¹², (16) -(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², (17)-(CH₂)_(n)C(O)NR¹¹R¹², (18) -(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², (19)-(CH₂)_(n)NR¹¹C(O)R¹², (20) -(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², (21)-(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹², (22) -(CH₂)_(n)NR¹¹CO₂R¹², and (23)-(CH₂)_(n)NR¹¹SO₂R¹², wherein alkyl, alkene, alkoxy, cycloalkyl, theheterocyclic ring, phenyl and —(CH₂)_(n) are unsubstituted orsubstituted with one to eight substituents selected from oxo, halogen,—C₁₋₆alkyl, —C₁₋₆alkoxy, phenyl, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, provided that at least one of R⁹ andR¹⁶ is selected from the group consisting of: —C₂₋₆alkene-CO₂R¹²,—(CH₂)_(n)C(O)R¹², —(CH₂)_(n)CO₂R¹², —(CH₂)_(n)OC(O)R¹²,—(CH₂)_(n)O(CH₂)_(n)CO₂R¹², —(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)NR¹¹C(O)R¹², —(CH₂)_(n)NR¹¹C(O)NR¹¹R¹²,—(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹CO₂R¹², and—(CH₂)_(n)NR¹¹SO₂R¹²; each R¹⁰ is independently selected from the groupconsisting of: (1) aryl, and (2) heteroaryl, wherein each aryl andheteroaryl ring is unsubstituted or substituted with one to four R¹⁴substituents; each R¹¹, R¹² and R¹³ is independently selected from thegroup consisting of: (1) hydrogen, (2) —C₁₋₈alkyl, (3) —(CH₂)_(n)OH, (4)—(CH₂)_(n)C₃₋₈cycloalkyl, (5) —(CH₂)_(n)C₂₋₈ heterocycloalkyl, (6)—(CH₂)_(n)aryl, and (7) —(CH₂)_(n)heteroaryl, wherein alkyl, cycloalkyl,heterocycloalkyl, and —(CH₂), are unsubstituted or substituted with oneto eight substituents selected from oxo, halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, and wherein aryl and heteroaryl are unsubstituted orsubstituted with one to eight substituents independently selected fromhalogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, or R¹¹ and R¹² together with thenitrogen to which they are attached form a 4-8 membered heterocyclicring containing 0-2 additional heteroatoms selected from oxygen, sulfur,and NR¹⁵, and wherein the 4-8 membered heterocyclic ring isunsubstituted or substituted with one to five substituents independentlyselected from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH,—(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H,—(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene and alkyl and alkoxyare unsubstituted or substituted with one to five substituents selectedfrom halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl; each R¹⁴ isindependently selected from the group consisting of: (1) hydrogen, (2)—(CH₂)_(n)halogen, (3) —(CH₂)_(n)CN, (4) —(CH₂)_(n)NO₂, (5)—(CH₂)_(n)OR¹³, (6) —C₂₋₆alkene-CO₂R¹², (7) —(CH₂)_(n)COR¹³, (8)—(CH₂)_(n)CO₂R¹³, (9) —(CH₂)_(n)C(O)NR¹¹R¹², (10) —(CH₂)_(n)CONR¹¹COR¹³,(11) —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹³, (12)—(CH₂)_(n)C(O)NR¹¹CH(CO₂R¹³)₂, (13) —(CH₂)_(n)NR¹¹R¹², (14)—(CH₂)_(n)NR¹³C(O)NR¹¹R¹², (15) —(CH₂)_(n)NR¹³C(O)R¹³, (16)—(CH₂)_(n)OC(O)NR¹¹R¹², (17) —(CH₂)_(n)NR¹³CO₂R¹³, (18)—(CH₂)_(n)NR¹³SO₂R¹³, (19) —(CH₂)_(n)SO₂NR¹¹R¹², (20) —(CH₂)_(n)SO₂R¹³,(21) —(CH₂)_(n)SO₃H, (22) —(CH₂)_(n)PO₂R¹³, (23) —(CH₂)_(n)PO₃H, (24)—C₁₋₆alkyl, (25) —(CH₂)_(n)aryl, (26) —(CH₂)_(n)heteroaryl, (27)—(CH₂)_(n)C₂₋₈heterocycloalkyl, and (28) —(CH₂)_(n)C₃₋₈cycloalkyl,wherein alkyl, cycloalkyl, heterocycloalkyl, and —(CH₂), areunsubstituted or substituted with one to five substituents selected fromoxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein alkene, aryland heteroaryl are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl; each R¹⁵ is independently selected from the groupconsisting of: (1) hydrogen, (2) —C₁₋₆alkyl, (3) —C₃₋₈cycloalkyl, (4)—SO₂R¹², (5) —COR¹³, and (6) —CO₂R¹², wherein alkyl and cycloalkyl areunsubstituted or substituted with one to six substituents selected fromhalogen, —OH, and —(CH₂)_(n)CO₂H; each n is independently 0, 1, 2, 3, 4,5, 6, 7 or 8; and each q is independently 1, 2, 3 or
 4. 2. The compoundof claim 1 wherein R⁸ is hydrogen; or a pharmaceutically acceptable saltthereof.
 3. The compound of claim 1 wherein X is N; or apharmaceutically acceptable salt thereof.
 4. The compound of claim 1wherein X is CR¹⁶; or a pharmaceutically acceptable salt thereof.
 5. Thecompound of claim 4 wherein R⁹ is hydrogen; or a pharmaceuticallyacceptable salt thereof.
 6. The compound of claim 1 wherein R¹⁰ isnaphthalene; or a pharmaceutically acceptable salt thereof.
 7. Thecompound of claim 1 wherein R¹⁰ is quinoline; or a pharmaceuticallyacceptable salt thereof.
 8. The compound of claim 1 wherein R⁹ isindependently selected from the group consisting of: hydrogen,—C₂₋₆alkene-CO₂R¹², —(CH₂)_(n)C(O)R¹², —(CH₂)_(n)CO₂R¹²,(CH₂)_(n)OC(O)R¹², —(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)NR¹¹CO₂R¹², —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)NR¹¹C(O)R¹², —(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², —(CH₂)_(n)NR¹¹SO₂R¹²,and —(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹², wherein alkene, and —(CH₂)_(n) areunsubstituted or substituted with one to eight substituents selectedfrom oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, phenyl, —(CH₂)_(n)OH,—(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H,—(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl andalkoxy are unsubstituted or substituted with one to five substituentsselected from halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, providedthat at least one of R⁹ and R¹⁶ is selected from the group consistingof: —C₂₋₆alkene-CO₂R¹², —(CH₂)_(n)C(O)R¹², —(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)OC(O)R¹², —(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹CO₂R¹²,—(CH₂)_(n)NR¹¹C(O)R¹², (CH₂)_(n)NR¹¹C(O)NR¹¹R¹²,—(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹², and —(CH₂)_(n)NR¹¹SO₂R¹²; or apharmaceutically acceptable salt thereof.
 9. The compound of claim 1 offormula III:

or a pharmaceutically acceptable salt thereof; wherein Y is N or CR¹⁴;R², R³ and R⁴ are each independently selected from the group consistingof: (1) hydrogen, (2) halogen, (3) —OH, (4) —C₁₋₆alkyl, (5) —C₁₋₆alkoxy,(6) —SC₁₋₆-alkyl, (7) —S(O)C₁₋₆-alkyl, (8) —S(O)₂C₁₋₆-alkyl, (9)—NHC₁₋₆-alkyl, and (10) —N(C₁₋₆-alkyl)₂, wherein alkyl and alkoxy areunsubstituted or substituted with one to five substituents selected fromhalogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy, and wherein R² and R³ or R³ andR⁴ together with the atoms to which they are attached may form a 4-8membered ring containing 0-2 heteroatoms independently selected fromoxygen, sulfur, and N—R¹⁵, and wherein the 4-8 membered ring isunsubstituted or substituted with a substituent selected from OH,halogen, C₁₋₆alkyl, and C₁₋₆alkoxy; R⁵, R⁶ and R⁷ are each independentlyselected from the group consisting of: (1) hydrogen, (2) halogen, (3)—OH, (4) —C₁₋₆alkyl, and (5) —C₁₋₆alkoxy, wherein alkyl and alkoxy areunsubstituted or substituted with one to five substituents independentlyselected from halogen, —OH, C₁₋₆alkyl, and C₁₋₆alkoxy; R⁸ isindependently selected from the group consisting of: (1) hydrogen, (2)halogen, (3) —C₁₋₆alkyl, (4) —C₁₋₆alkoxy, and (5) —C₃₋₆cycloalkyl; R⁹ isindependently selected from the group consisting of: (1)—C₂₋₆alkene-CO₂R¹², (2) —(CH₂)_(n)C(O)R¹², (3) —(CH₂)_(n)CO₂R¹², (4)—(CH₂)_(n)OC(O)R¹², (5) —(CH₂)_(n)O(CH₂)_(n)CO₂R¹², (6)—(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², (7) —(CH₂)_(n)C(O)NR¹¹R¹², (8)—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², (9) —(CH₂)_(n)NR¹¹C(O)R¹², (10)—(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², (11) —(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹², (12)—(CH₂)_(n)NR¹¹CO₂R¹², and (13) —(CH₂)_(n)NR¹¹SO₂R¹², wherein alkene, and—(CH₂)_(n) are unsubstituted or substituted with one to eightsubstituents selected from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy,phenyl, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl; each R¹¹, R¹² and R¹³ is independently selected from thegroup consisting of: (1) hydrogen, (2) —C₁₋₈alkyl, (3) —(CH₂)_(n)OH, (4)—(CH₂)_(n)C₃₋₈cycloalkyl, (5) —(CH₂)_(n)C₂₋₈heterocycloalkyl, (6)—(CH₂)_(n)aryl, and (7) —(CH₂)_(n)heteroaryl, wherein alkyl, cycloalkyl,heterocycloalkyl, —(CH₂)_(n) are unsubstituted or substituted with oneto eight substituents selected from oxo, halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, wherein aryl, and heteroaryl are unsubstituted orsubstituted with one to eight substituents independently selected fromhalogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, or R¹¹ and R¹² together with thenitrogen to which they are attached form a 4-8 membered heterocyclicring containing 0-2 additional heteroatoms selected from oxygen, sulfur,and NR¹⁵, and wherein the 4-8 membered heterocyclic ring isunsubstituted or substituted with one to five substituents independentlyselected from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH,—(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H,—(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene and alkyl and alkoxyare unsubstituted or substituted with one to five substituents selectedfrom halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl; each R¹⁴ isindependently selected from the group consisting of: (1) hydrogen, (2)—(CH₂)_(n)halogen, (3) —(CH₂)_(n)CN, (4) —(CH₂)_(n)NO₂, (5)—(CH₂)_(n)OR¹³, (6) —C₂₋₆alkene-CO₂R¹², (7) —(CH₂)_(n)COR¹³, (8)—(CH₂)_(n)CO₂R¹³, (9) —(CH₂)_(n)C(O)NR¹¹R¹², (10) —(CH₂)_(n)CONR¹¹COR¹³,(11) —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹³, (12)—(CH₂)_(n)C(O)NR¹¹CH(CO₂R¹³)₂, (13) —(CH₂)_(n)NR¹¹R¹², (14)—(CH₂)_(n)NR¹³C(O)NR¹¹R¹², (15) —(CH₂)_(n)NR¹³C(O)R¹³, (16)—(CH₂)_(n)OC(O)NR¹¹R¹², (17) —(CH₂)_(n)NR¹³CO₂R¹³, (18)—(CH₂)_(n)NR¹³SO₂R¹³, (19) —(CH₂)_(n)SO₂NR¹¹R¹², (20) —(CH₂)_(n)SO₂R¹³,(21) —(CH₂)_(n)SO₃H, (22) —(CH₂)_(n)PO₂R¹³, (23) —(CH₂)_(n)PO₃H, (24)—C₁₋₆alkyl, (25) —(CH₂)_(n)aryl, (26) —(CH₂)_(n)heteroaryl, (27)—(CH₂)_(n)C₂₋₈heterocycloalkyl, and (28) —(CH₂)_(n)C₃₋₈cycloalkyl,wherein alkyl, cycloalkyl, heterocycloalkyl, and —(CH₂), areunsubstituted or substituted with one to five substituents selected fromoxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein alkene, aryland heteroaryl are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl; each R¹⁵ is independently selected from the groupconsisting of: (1) hydrogen, (2) —C₁₋₆alkyl, unsubstituted orsubstituted with one to six halogens, (3) —C₃₋₈cycloalkyl, unsubstitutedor substituted with one to six halogens, (4) —SO₂R¹², (5) —COR¹², and(6) —CO₂R¹²; each m is independently 0, 1, 2, 3 or 4; each n isindependently 0, 1, 2, 3, 4, 5, 6, 7 or 8; each p is independently 0, 1,2, or 3; and each q is independently 1, 2, 3 or
 4. 10. The compound ofclaim 9 wherein p is 0; or a pharmaceutically acceptable salt thereof.11. The compound of claim 1 of formula IV:

or a pharmaceutically acceptable salt thereof; wherein Y is N or CR¹⁴;R², R³ and R⁴ are each independently selected from the group consistingof: (1) hydrogen, (2) halogen, (3) —OH, (4) —C₁₋₆alkyl, (5) —C₁₋₆alkoxy,(6) —SC₁₋₆-alkyl, (7) —S(O)C₁₋₆-alkyl, (8) —S(O)₂C₁₋₆-alkyl, (9)—NHC₁₋₆-alkyl, and (10) —N(C₁₋₆-alkyl)₂, wherein alkyl and alkoxy areunsubstituted or substituted with one to five substituents selected fromhalogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy, or R² and R³ or R³ and R⁴together with the atoms to which they are attached may form a 4-8membered ring containing 0-2 heteroatoms independently selected fromoxygen, sulfur, and N—R¹⁵, and wherein the 4-8 membered ring isunsubstituted or substituted with a substituent selected from OH,halogen, C₁₋₆alkyl, and C₁₋₆alkoxy; R⁵, R⁶ and R⁷ are each independentlyselected from the group consisting of: (1) hydrogen, (2) halogen, (3)—OH, (4) —C₁₋₆alkyl, and (5) —C₁₋₆alkoxy, wherein alkyl and alkoxy areunsubstituted or substituted with one to five substituents independentlyselected from halogen, —OH, C₁₋₆alkyl, and C₁₋₆alkoxy; R⁸ isindependently selected from the group consisting of: (1) hydrogen, (2)halogen, (3) —C₁₋₆alkyl, (4) —C₁₋₆alkoxy, and (5) —C₃₋₆cycloalkyl; R⁹and R¹⁶ are each independently selected from the group consisting of:(1) hydrogen, (2) -(CH₂)_(n)CF₃, (3) -(CH₂)_(n)OH, (4) -(CH₂)_(n)CN, (5)-C₁₋₆alkyl, (6) -C₁₋₆alkoxy, (7) -(CH₂)_(n)C₃₋₈cycloalkyl, (8)-(CH₂)_(n)NR¹¹R¹², (9) -a 5-10 membered aromatic monocyclic or bicyclicheterocyclic ring, (10) phenyl, (11) -C₂₋₆alkene-CO₂R¹², (12)-(CH₂)_(n)C(O)R¹², (13) -(CH₂)_(n)CO₂R¹², (14) -(CH₂)_(n)OC(O)R¹², (15)-(CH₂)_(n)O(CH₂)_(n)CO₂R¹², (16) -(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², (17)-(CH₂)_(n)C(O)NR¹¹R¹², (18) -(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², (19)-(CH₂)_(n)NR¹¹C(O)R¹², (20) -(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², (21)-(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹², (22) -(CH₂)_(n)NR¹¹CO₂R¹², and (23)-(CH₂)_(n)NR¹¹SO₂R¹², wherein alkyl, alkene, alkoxy, cycloalkyl, theheterocyclic ring, phenyl and —(CH₂)_(n) are unsubstituted orsubstituted with one to eight substituents selected from oxo, halogen,—C₁₋₆alkyl, —C₁₋₆alkoxy, phenyl, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, provided that at least one of R⁹ andR¹⁶ is selected from the group consisting of: —C₂₋₆alkene-CO₂R¹²,—(CH₂)_(n)C(O)R¹², —(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)OC(O)R¹²—(CH₂)_(n)O(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)O(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)C(O)NR¹¹R¹²,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)NR¹¹C(O)R¹²,—(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², —(CH₂)_(n)NR¹¹(CH₂)_(n)CO₂R¹²,—(CH₂)_(n)NR¹¹CO₂R¹², and —(CH₂)_(n)NR¹¹SO₂R¹²; each R¹¹, R¹² and R¹³ isindependently selected from the group consisting of: (1) hydrogen, (2)—C₁₋₈alkyl, (3) —(CH₂)_(n)OH, (4) —(CH₂)_(n)C₃₋₈cycloalkyl, (5)—(CH₂)_(n)C₂₋₈heterocycloalkyl, (6) —(CH₂)_(n)aryl, and (7)—(CH₂)_(n)heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, and—(CH₂), are unsubstituted or substituted with one to eight substituentsselected from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH,—(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H,—(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl andalkoxy are unsubstituted or substituted with one to five substituentsselected from halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and whereinaryl and heteroaryl are unsubstituted or substituted with one to eightsubstituents independently selected from halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, or R¹¹ and R¹² together with the nitrogen to which theyare attached form a 4-8 membered heterocyclic ring containing 0-2additional heteroatoms selected from oxygen, sulfur, and NR¹⁵, andwherein the 4-8 membered heterocyclic ring is unsubstituted orsubstituted with one to five substituents independently selected fromoxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl; each R¹⁴ is independently selected fromthe group consisting of: (1) hydrogen, (2) —(CH₂)_(n)halogen, (3)—(CH₂)_(n)CN, (4) —(CH₂)_(n)NO₂, (5) —(CH₂)_(n)OR¹³, (6)—C₂₋₆alkene-CO₂R¹², (7) —(CH₂)_(n)COR¹³, (8) —(CH₂)_(n)CO₂R¹³, (9)—(CH₂)_(n)C(O)NR¹¹R¹², (10) —(CH₂)_(n)CONR¹¹COR¹³, (11)—(CH₂)_(n)C(O)NR¹¹ (CH₂)_(n)CO₂R¹³, (12) —(CH₂)_(n)C(O)NR¹¹CH(CO₂R¹³)₂,(13) —(CH₂)_(n)NR¹¹R¹², (14) —(CH₂)_(n)NR¹³C(O)NR¹¹R¹², (15)—(CH₂)_(n)NR¹³C(O)R¹³, (16) —(CH₂)_(n)OC(O)NR¹¹R¹², (17)—(CH₂)_(n)NR¹³CO₂R¹³, (18) —(CH₂)_(n)NR¹³SO₂R¹³, (19)—(CH₂)_(n)SO₂NR¹¹R¹², (20) —(CH₂)_(n)SO₂R¹³, (21) —(CH₂)_(n)SO₃H, (22)—(CH₂)_(n)PO₂R¹³, (23) —(CH₂)_(n)PO₃H, (24) —C₁₋₆alkyl, (25)—(CH₂)_(n)aryl, (26) —(CH₂)_(n)heteroaryl, (27)—(CH₂)_(n)C₂₋₈heterocycloalkyl, and (28) —(CH₂)_(n)C₃₋₈cycloalkyl,wherein alkyl, cycloalkyl, heterocycloalkyl, and —(CH₂)_(n) areunsubstituted or substituted with one to five substituents selected fromoxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein alkene, aryland heteroaryl are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl; each R¹⁵ is independently selected from the groupconsisting of: (1) hydrogen, (2) —C₁₋₆alkyl, unsubstituted orsubstituted with one to six halogens, (3) —C₃₋₈cycloalkyl, unsubstitutedor substituted with one to six halogens, (4) —SO₂R¹², (5) —COR¹², and(6) —CO₂R¹²; each m is independently 0, 1, 2, 3 or 4; each n isindependently 0, 1, 2, 3, 4, 5, 6, 7 or 8; each p is independently 0, 1,2, or 3; and each q is independently 1, 2, 3 or
 4. 12. The compound ofclaim 11 wherein p is 0; or a pharmaceutically acceptable salt thereof.13. The compound of claim 1 selected from the group consisting of: (1)3-{(3S)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoicacid, (2)3-{(3S)-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoicacid, (3)3-((3R)-3-[(acetylamino)methyl]-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid, (4)3-[1-{[1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperidin-4-yl]propanoicacid, (5)(2S)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(3-quinolinyl)-2-piperazinecarboxylicacid, trifluoroacetic acid salt, (6)(2S)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(3-quinolinyl)-2-ethyl-4-(3-quinolinyl)-2-piperazinecarboxamide,trifluoroacetic acid salt, (7)N-{[(2S)-1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(3-quinolinyl)-2-piperazinyl]carbonyl}glycine, (8){[(2S)-1-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(3-quinolinyl)-2-piperazinyl]methoxy}aceticacid, (9)3-((3R)-4-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-{[2-(methylamino)-2-oxoethoxy]methyl}-1-piperazinyl)-1-naphthoicacid, (10)3-((3R)-4-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-{[2-(methylamino)-2-oxoethoxy]methyl}-1-piperazinyl)-1-naphthoicacid, and (11)(2S)-4-(4-Carboxy-2-naphthyl)-1-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-2-piperazinecarboxylicacid; or a pharmaceutically acceptable salt thereof.
 14. The compound ofclaim 13 selected from the group consisting of:3-{(3S)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoicacid, or a pharmaceutically acceptable salt thereof.
 15. The compound ofclaim 13 selected from the group consisting of:3-{(3S)-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-[(isopropylamino)carbonyl]-1-piperazinyl}-1-naphthoicacid, or a pharmaceutically acceptable salt thereof.
 16. The compound ofclaim 13 selected from the group consisting of:3-((3R)-3-[(acetylamino)methyl]-4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid, or a pharmaceutically acceptable salt thereof.
 17. The compound ofclaim 13 selected from the group consisting of:3-[1-{[1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperidin-4-yl]propanoicacid; or a pharmaceutically acceptable salt thereof.
 18. The compound ofclaim 13 wherein the pharmaceutically acceptable salt thereof is atrifluoroacetic acid salt.
 19. A pharmaceutical composition whichcomprises a compound of claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier. 20-22. (canceled)23. A method for the treatment of obesity, diabetes, or an obesityrelated disorder in a subject in need thereof which comprisesadministering to said subject a therapeutically effective amount of acompound according to claim 1, or a pharmaceutically acceptable saltthereof.